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Dietz MV, Ziekman MJ, van Kooten JP, Brandt-Kerkhof ARM, van Meerten E, Verhoef C, Madsen EVE. Treatment and Survival Outcomes for Patients with Colorectal Peritoneal Metastases Deemed Ineligible for Cytoreductive Surgery (CRS) with Hyperthermic Intraperitoneal Chemotherapy (HIPEC): Results of a Retrospective Study. Ann Surg Oncol 2023; 30:2048-2056. [PMID: 36566258 DOI: 10.1245/s10434-022-12969-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 12/08/2022] [Indexed: 12/25/2022]
Abstract
BACKGROUND Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is a treatment option for selected patients with colorectal peritoneal metastases (PM). This report provides an overview of treatment and survival outcomes for patients deemed ineligible for CRS-HIPEC. METHODS Colorectal PM patients referred to a tertiary center from 2014 to 2020 that were ineligible for CRS-HIPEC were included. Patient, tumor, and treatment characteristics were provided. Survival analyses were performed using the Kaplan-Meier method. RESULTS Of 476 patients referred for CRS-HIPEC, 227 (48%) were deemed ineligible. Median follow-up was 15 months [IQR 10-22]. Data on follow-up treatment was available for 198 patients, of which 73% received systemic therapy. These patients had a median overall survival (OS) of 17 months [IQR 9-25]. For patients receiving best supportive care (BSC) median OS was 4 months [IQR 2-9]. The main reason for ineligibility was extensive PM (42%), with a median OS of 11 months [IQR 5-18]. Patients deemed ineligible due to (extensive) liver (9%) or lung metastases (8%) showed longer OS (median 22 months, IQR 8-27, and 24 months, IQR 12-29, respectively) than patients with extensive PM (median 11 months, IQR 5-18) or distant lymph node metastases (median 14 months, IQR 4-25). CONCLUSION The main reason for CRS-HIPEC ineligibility was extensive PM. The majority of patients received systemic therapy. Patients deemed ineligible due to extra-peritoneal metastases had better survival outcomes than patients deemed ineligible due to extensive PM.
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Affiliation(s)
- Michelle V Dietz
- Department of Surgical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
| | - Merijn J Ziekman
- Department of Surgical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Job P van Kooten
- Department of Surgical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | | | - Esther van Meerten
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Cornelis Verhoef
- Department of Surgical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Eva V E Madsen
- Department of Surgical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
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Outcomes Following Treatment with FOLFOX for Patients with Resectable or Potentially Resectable Metastatic Colorectal Cancer: A Population-based Cohort Study. Clin Oncol (R Coll Radiol) 2023; 35:188-198. [PMID: 36610878 DOI: 10.1016/j.clon.2022.12.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 10/12/2022] [Accepted: 12/19/2022] [Indexed: 01/07/2023]
Abstract
AIMS To evaluate the safety and effectiveness of oxaliplatin-based combination chemotherapy for patients with metastatic colorectal cancer (mCRC) to extrahepatic sites. MATERIALS AND METHODS We conducted a population-based retrospective study examining the safety and effectiveness of perioperative oxaliplatin for resectable or potentially resectable colorectal metastases in Ontario, Canada. Outcomes were also compared with patients with liver-only metastases. Patients received oxaliplatin for mCRC between 1 January 2013 and 30 June 2020. RESULTS In total, 192 patients had extrahepatic metastases. Seventy per cent had R0 metastasectomy. The 3-year disease-free survival and overall survival were 62% and 79%, respectively; <4% of patients died within 60 days of metastasectomy and 74-90% of patients received treatment according to recommendations from a multidisciplinary setting. Compared with liver-only controls (n = 1306), patients had mCRC to the lung only (n = 115), lung and liver (n = 55) and liver with non-pulmonary site (n = 22). Extrahepatic metastases were more likely to be found for patients whose primary colorectal resection had positive margins (14% versus 7%, P = 0.005) and primary tumours located in the rectum [odds ratio 4.01 (2.31-6.97)]. After adjustment, there was no difference in overall survival between liver-only controls and patients with lung-only [hazard ratio 0.82 (0.59-1.15)] or liver and lung metastases [hazard ratio 1.26 (0.85-1.87)] (P = 0.24). In total, 79/115 (69%) of patients with lung-only metastases had a metastasectomy compared with 645/1306 (49%) and 15/55 (27%) of patients with liver-only and liver and lung metastases, respectively. Hospital visits were similar between patients with liver-only and extrahepatic metastases. CONCLUSION Oxaliplatin-based chemotherapy for patients with resectable or potentially resectable mCRC with extrahepatic metastases was safe and resulted in similar outcomes in appropriately selected patients when compared with patients with liver-only metastases.
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Zhou H, Wang Y, Zhang Z, Xiong L, Liu Z, Wen Y. A novel prognostic gene set for colon adenocarcinoma relative to the tumor microenvironment, chemotherapy, and immune therapy. Front Genet 2023; 13:975404. [PMID: 36699444 PMCID: PMC9868701 DOI: 10.3389/fgene.2022.975404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 12/21/2022] [Indexed: 01/11/2023] Open
Abstract
Background: Colon adenocarcinoma (COAD) is a common aggressive malignant tumor. Heterogeneity in tumorigenesis and therapy response leads to an unsatisfactory overall survival of colon adenocarcinoma patients. Our study aimed to identify tools for a better prediction of colon adenocarcinoma prognosis, bolstering the development of a better personalized treatment and management. Method: We used the least absolute shrinkage and selection operator (LASSO) Cox model to analyze the prognosis-related gene datasets from the Gene Expression Omnibus (GEO) database and verified them using The Cancer Genome Atlas (TCGA) database. The area under the curve (AUC) was calculated using the receiver operating characteristic (ROC) curve to evaluate the predictive ability of the risk score model. Gene Set Enrichment Analysis (GSEA) was used to identify the significantly enriched and depleted biological processes. The tumor immune dysfunction and exclusion (TIDE) algorithm was taken to explore the relationship between the risk score and immunotherapy. The observations collectively helped us construct a nomogram to predict prognosis. Finally, the correlation between drug sensitivity and prognostic gene sets was conducted based on the Cancer Therapeutics Response Portal (CTRP) analyses. Results: We constructed a scoring model to assess the significance of the prognosis risk-related gene signatures, which was relative to common tumor characteristics and tumor mutational burdens. Patients with a high-risk score had higher tumor stage and poor prognosis (p< 0.05). Moreover, the expressions of these genes were in correlation with changes in the tumor microenvironment (TME). The risk score is an independent prognostic factor for COAD (p< 0.05). The accuracy of the novel nomogram model with a risk score and TNM-stage prediction prognosis in the predicting prognosis was higher than that of the TNM stage. Further analysis showed that a high-risk score was associated with tumor immune rejection. Patients with a low-risk score have a better prognosis with chemotherapy than those with a high-risk score. Compared to patients in the high-risk group, patients in the low-risk group had a significant survival advantage after receiving chemotherapy. In addition, the prognostic gene sets aid the assessment of drug sensitivity. Conclusion: This study establishes a new prognostic model to better predict the clinical outcome and TME characteristics of colon adenocarcinoma. We believe, our model also serves as a useful clinical tool to strengthen the functioning of chemotherapy, immunotherapy, and targeted drugs.
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Affiliation(s)
| | | | | | | | | | - Yu Wen
- *Correspondence: Zhongtao Liu, ; Yu Wen,
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4
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Targeting Annexin A1 as a Druggable Player to Enhance the Anti-Tumor Role of Honokiol in Colon Cancer through Autophagic Pathway. Pharmaceuticals (Basel) 2023; 16:ph16010070. [PMID: 36678567 PMCID: PMC9862434 DOI: 10.3390/ph16010070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 12/27/2022] [Accepted: 12/29/2022] [Indexed: 01/03/2023] Open
Abstract
Colon cancer is one of the most common digestive tract malignancies, having the second highest mortality rate among all tumors, with a five-year survival of advanced patients of only 10%. Efficient, targeted drugs are still lacking in treating colon cancer, so it is urgent to explore novel druggable targets. Here, we demonstrated that annexin A1 (ANXA1) was overexpressed in tumors of 50% of colon cancer patients, and ANXA1 overexpression was significantly negatively correlated with the poor prognosis of colon cancer. ANXA1 promoted the abnormal proliferation of colon cancer cells in vitro and in vivo by regulating the cell cycle, while the knockdown of ANXA1 almost totally inhibited the growth of colon cancer cells in vivo. Furthermore, ANXA1 antagonized the autophagic death of honokiol in colon cancer cells via stabilizing mitochondrial reactive oxygen species. Based on these results, we speculated that ANXA1 might be a druggable target to control colon cancer and overcome drug resistance.
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Zhang C, Cao C, Liu L, Lv Y, Li J, Lu J, Wang S, Du B, Yang X. Effect of primary tumor resection on survival in patients with asymptomatic unresectable metastatic colorectal cancer: a systematic review and meta-analysis. Expert Rev Anticancer Ther 2023; 23:107-115. [PMID: 36397266 DOI: 10.1080/14737140.2023.2149497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
OBJECTIVE It remains controversial whether primary tumor resection (PTR) improves survival in patients with asymptomatic, unresectable metastatic colorectal cancer (mCRC). Therefore, we conducted a meta-analysis to assess the latest evidence on clinical outcomes. MATERIALS AND METHODS We systematically searched PubMed, Web of Science, Cochrane Library, and Embase databases for eligible studies published between database inception and May 2022. RevMan 5.4 and Stata 16.0 were used for the meta-analysis. RESULTS A total of nine studies were included, including four randomized controlled trials (RCTs) and five retrospective cohort studies. Meta-analysis showed that overall survival (OS) [HR = 0.89, 95%CI (0.74, 1.06), P = 0.19] and progression-free survival (PFS) [HR = 0.87, 95%CI (0.71, 1.06), P = 0.17] were not significantly different between the PTR and non-PTR groups. In the subgroup analysis, all subgroups showed no significant difference in OS between the two groups. CONCLUSION PTR may not provide additional survival benefits over chemotherapy in asymptomatic, unresectable mCRC patients. However, in view of the limitations of this study, more well-designed RCTs are needed to validate our conclusions.
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Affiliation(s)
- Chengren Zhang
- Clinical Medical College of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region, China.,Department of Anorectal Surgery, Gansu Provincial Hospital, Lanzhou, Gansu province, China.,Anorectal Disease Research Center, Gansu Provincial People's Hospital, Lanzhou, Gansu province, China
| | - Cong Cao
- Clinical Medical College of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region, China.,Department of Anorectal Surgery, Gansu Provincial Hospital, Lanzhou, Gansu province, China.,Anorectal Disease Research Center, Gansu Provincial People's Hospital, Lanzhou, Gansu province, China
| | - Lili Liu
- Department of First Clinical Medical College of Gansu University of Chinese Medicine, Lanzhou, Gansu province, China
| | - Yaochun Lv
- Department of Anorectal Surgery, Gansu Provincial Hospital, Lanzhou, Gansu province, China.,Anorectal Disease Research Center, Gansu Provincial People's Hospital, Lanzhou, Gansu province, China
| | - Jingjing Li
- Clinical Medical College of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region, China.,Department of Anorectal Surgery, Gansu Provincial Hospital, Lanzhou, Gansu province, China.,Anorectal Disease Research Center, Gansu Provincial People's Hospital, Lanzhou, Gansu province, China
| | - Jiyong Lu
- Department of Anorectal Surgery, Gansu Provincial Hospital, Lanzhou, Gansu province, China.,Anorectal Disease Research Center, Gansu Provincial People's Hospital, Lanzhou, Gansu province, China.,Department of First Clinical Medical College of Gansu University of Chinese Medicine, Lanzhou, Gansu province, China
| | - Shuai Wang
- Department of Anorectal Surgery, Gansu Provincial Hospital, Lanzhou, Gansu province, China.,Anorectal Disease Research Center, Gansu Provincial People's Hospital, Lanzhou, Gansu province, China.,Department of First Clinical Medical College of Gansu University of Chinese Medicine, Lanzhou, Gansu province, China
| | - Binbin Du
- Department of Anorectal Surgery, Gansu Provincial Hospital, Lanzhou, Gansu province, China.,Anorectal Disease Research Center, Gansu Provincial People's Hospital, Lanzhou, Gansu province, China
| | - Xiongfei Yang
- Department of Anorectal Surgery, Gansu Provincial Hospital, Lanzhou, Gansu province, China.,Anorectal Disease Research Center, Gansu Provincial People's Hospital, Lanzhou, Gansu province, China
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Rasbach E, Birgin E, Betzler A, Rahbari NN, Reissfelder C. Therapiestrategien beim synchron metastasierten Kolonkarzinom. COLOPROCTOLOGY 2022. [DOI: 10.1007/s00053-022-00601-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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7
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Huang L, Wei G, Chen N, Liu J, Wang Z, Yu Y, Qiu M. Impact of Upfront Chemotherapy on the Effect of Primary Tumour Resection for Asymptomatic Synchronous Colorectal Cancer With Unresectable Metastases: A Propensity-Score-Matched Cohort Analysis. Clin Med Insights Oncol 2022; 16:11795549221085054. [PMID: 35355515 PMCID: PMC8958687 DOI: 10.1177/11795549221085054] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 02/05/2022] [Indexed: 02/05/2023] Open
Abstract
Background: It is controversial whether primary tumour resection (PTR) and the sequencing of chemotherapy and PTR are associated with the survival of patients with incurable stage IV colorectal cancer. This study aimed to explore the effects of PTR and the sequencing of chemotherapy and PTR on asymptomatic colorectal cancer with synchronous unresectable metastases (asmCRC). Patients and Methods: Patients with asmCRC were retrospectively identified from a single centre and categorised into 3 groups: PTR followed by chemotherapy (POC), upfront chemotherapy followed by PTR (UFC), and palliative chemotherapy (PC). The primary end points included median overall survival (OS) and progression-free survival (PFS). Clinical features were analysed using χ2 test, while survival curves were generated using the Kaplan-Meier test. Propensity-score matching (PSM) was performed when comparing survival between POC and UFC groups. Results: From 2008 to 2014, 255 patients were identified and included into the POC (n = 101), UFC (n = 40), and PC (n = 114) groups. The UFC and POC groups had significantly better median OS compared with the PC group (40.7 vs 16.3 months, P < .0001; 39.7 vs 16.3 months, P < .0001). Before PSM, the UFC group had better median PFS than the POC and PC groups (18.5 vs 9.7 months, P = .038; 18.5 vs 6.1 months, P < .0001). After PSM, UFC has better PFS than POC (P = .038). And the UFC group did not have higher postoperative or preoperative morbidity compared with the POC group (P = .235). Conclusions: Primary tumour resection could improve the survival of patients with asmCRC. Compared with POC or PC, UFC was associated with a better median PFS without significantly increasing preoperative or postoperative morbidity.
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Affiliation(s)
- Lin Huang
- Lung Cancer Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Guixia Wei
- Department of Abdominal Cancer, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Nan Chen
- Department of Thoracic Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Jiewei Liu
- Lung Cancer Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Ziqiang Wang
- Department of Gastrointestinal Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Yongyang Yu
- Department of Gastrointestinal Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Meng Qiu
- Department of Abdominal Cancer, West China Hospital of Sichuan University, Chengdu, Sichuan, China
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8
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Missing data handling technique in joint modeling context. BIOMEDICAL ENGINEERING ADVANCES 2021. [DOI: 10.1016/j.bea.2021.100012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
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9
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Harrison OJ, Sarvananthan S, Tamburrini A, Peebles C, Alzetani A. Image-guided combined ablation and resection in thoracic surgery for the treatment of multiple pulmonary metastases: A preliminary case series. JTCVS Tech 2021; 9:156-162. [PMID: 34647088 PMCID: PMC8500989 DOI: 10.1016/j.xjtc.2021.03.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 03/10/2021] [Indexed: 11/29/2022] Open
Abstract
Objectives To demonstrate the feasibility and preliminary outcomes of a novel hybrid technique combining percutaneous microwave ablation and wire-assisted wedge resection for patients with multiple pulmonary metastases using intraoperative imaging. Methods We describe our technique and present a retrospective case series of 4 patients undergoing iCART at our institution between August 2018 and January 2020. Procedures were performed in a hybrid operating suite using the ARTIS Pheno cone beam computerized tomography scanner (Siemens Healthineers, Erlangen, German). Patient information included past history of malignancy as well as lesion size, depth, location, and histology result. Surgical complications and length of stay were also recorded. Results Five procedures were performed on 4 patients during the study period. One patient underwent bilateral procedures 4 weeks apart. All patients underwent at least 1 ablation and 1 wedge resection during the combined procedure. Patient ages ranged from 40 to 66 years and the majority (75%) were men. All had a past history of cancer. Lesions were treated in every lobe. Size and depth ranged from 6 to 24 mm and 21 to 33 mm, respectively, for ablated nodules and 5 to 27 mm and 0 to 22 mm, respectively, for the wedge resected nodules. Three procedures were completed uniportal and operative time ranged from 51 to 210 minutes. All cases sustained <10 mL blood loss. There were 2 intraoperative pneumothorax, 1 prevented successful completion of the ablation. One patient required a prolonged period of postoperative physiotherapy and was discharged on day 6. The other patients were discharged on postoperative day 2 or 3. All 5 histology specimens confirmed metastatic disease. Conclusions Our hybrid approach provides a minimally invasive and comprehensive personalized therapy for patients with multiple pulmonary metastases under a single general anesthetic. It provides histology-based diagnosis whilst minimizing lung tissue loss and eliminating the need for transfer from radiology to operating theatre. Emergence of ablation as a treatment for stage 1 non–small cell lung cancer and the expansion of lung cancer screening may widen the application of iCART in the future.
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Affiliation(s)
- Oliver J Harrison
- Department of Thoracic Surgery, University Hospital Southampton, Southampton, United Kingdom
| | - Sajiram Sarvananthan
- Department of Thoracic Surgery, University Hospital Southampton, Southampton, United Kingdom
| | - Alessandro Tamburrini
- Department of Thoracic Surgery, University Hospital Southampton, Southampton, United Kingdom
| | - Charles Peebles
- Department of Cardiothoracic Radiology, University Hospital Southampton, Southampton, United Kingdom
| | - Aiman Alzetani
- Department of Thoracic Surgery, University Hospital Southampton, Southampton, United Kingdom
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10
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Clinical Factors Affecting Bevacizumab Efficacy With and Without Conventional Chemotherapy in Metastatic Colon Cancer. Am J Ther 2021; 27:e500-e506. [PMID: 32902937 DOI: 10.1097/mjt.0000000000000859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE Bevacizumab (BZ) combined with first line chemotherapy (CC) has shown good clinical outcomes in metastatic colorectal cancer (mCRC). Overall survival (OS) and/or progression free survival in mCRC patients receiving BZ with or without 5FU-based CC is thought to be affected by clinical and morphological factor(s). PATIENTS AND METHODS We reviewed retrospective medical records of all consecutive mCRC patients treated with BZ with or without CC at tertiary care center between 2003 and 2009 out of which149 patients (m = 77, f = 72) were eligible. RESULTS Our study population had a mean age at diagnosis of 63.5 years (SD = 11) with median follow-up period of 19.4 months. On initial radiological evaluation following BZ therapy, 56 patients (m = 31, f = 25) had complete or partial response categorized as "early responders." Remaining patients (m = 46, f = 47) who were either stable or showed progressive disease were categorized as "non-responders." Fifty percent among early responders and 60% among non-responders [relative risk (RR) 0.67 (95% confidence interval (CI), 0.43-1.06)] demonstrated disease progression on follow up. There was a slightly better OS among early responders compared to non-responders (median 21.5 months days versus 16.8 months, P = 0.07). Cox regression analysis suggested male sex (RR 0.65, 95% CI, 0.43-0.98), hematochezia (RR 0.63, 95% CI, 0.4-0.98), resectable primary tumor (RR 0.42, 95% CI, 0.24-0.72) and resectable metastatic mass (RR 0.32, 95% CI, 0.14-0.74) were found to be associated with longer OS. Abdominal pain (RR 1.76, 95% CI, 1.1-2.8), accompanying diabetes (RR 1.76, 95% CI, 1.09-2.85), and unexplained weight loss (RR 2.73, 95% CI, 1.73-4.29) were associated with poor OS. CONCLUSIONS Better OS among mCRC patients with resectable primary and metastatic tumors was seen. This is the first study to demonstrate slightly better outcome in males and negative influence of diabetes on outcome in mCRC treated with BZ.
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Dunn C, Hong W, Gibbs P, Ackland S, Sjoquist K, Tebbutt NC, Price T, Burge M. Personalizing First-Line Systemic Therapy in Metastatic Colorectal Cancer: Is There a Role for Initial Low-Intensity Therapy in 2021 and Beyond? A Perspective From Members of the Australasian Gastrointestinal Trials Group. Clin Colorectal Cancer 2021; 20:245-255. [PMID: 34103264 DOI: 10.1016/j.clcc.2021.05.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 04/16/2021] [Accepted: 05/02/2021] [Indexed: 01/18/2023]
Abstract
Palliative chemotherapy is the cornerstone of treatment for the majority of patients with metastatic colorectal cancer, with the aim of increasing length and quality of life. Although guidelines outline the available treatment options in the first line, they provide limited guidance on choice and intensity of the chemotherapy backbone. Data from the TRIBE and TRIBE2 studies confirm a survival benefit with triplet FOLFOXIRI and bevacizumab, and this is a preferred option for younger patients with good performance status able to tolerate it. However, the relative benefit of a fluoropyrimidine doublet with oxaliplatin or irinotecan over single-agent fluoropyrimidine with or without a biologic is less certain; the available data demonstrate that single-agent fluoropyrimidine plus a biologic with planned sequencing of subsequent agents can produce similar overall survival outcomes with reduced toxicity. Our analysis of local real-world registry data suggests that this is an underutilized approach, particularly in younger and fitter patients. Established prognostic factors, including patient age, performance status, tumor sidedness, and biomarkers such as RAS/BRAF, are key in treatment selection; patients with left-sided RAS/BRAF wild-type disease or patients with low tumor bulk may be ideal for a less intensive regimen. Further studies are required to confirm the value of less-intensive regimens in the modern era, where the incorporation of biologic therapies has become routine and where non-chemotherapy options are emerging as viable options for molecularly defined patient subsets.
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Affiliation(s)
- Catherine Dunn
- Gibbs Lab, Personalised Medicine Division, Walter and Eliza Hall Institute, Melbourne, Victoria, Australia.
| | - Wei Hong
- Gibbs Lab, Personalised Medicine Division, Walter and Eliza Hall Institute, Melbourne, Victoria, Australia
| | - Peter Gibbs
- Gibbs Lab, Personalised Medicine Division, Walter and Eliza Hall Institute, Melbourne, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia; Department of Medical Oncology, Western Health, Melbourne, Victoria, Australia
| | - Stephen Ackland
- Faculty of Health and Medicine, University of Newcastle, Newcastle, New South Wales, Australia; Hunter Medical Research Institute, Newcastle, New South Wales, Australia
| | - Katrin Sjoquist
- NHMRC Clinical Trials Centre, University of Sydney, Sydney, New South Wales, Australia; Cancer Care Centre, St. George Hospital, Kogarah, New South Wales, Australia
| | - Niall C Tebbutt
- Department of Medical Oncology, Austin Health, Melbourne, Victoria, Australia; Department of Surgery, University of Melbourne, Melbourne, Victoria, Australia
| | - Timothy Price
- Department of Medical Oncology, The Queen Elizabeth Hospital, Woodville, South Australia, Australia
| | - Matthew Burge
- Department of Medical Oncology, Royal Brisbane Hospital, Herston, Queensland, Australia
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12
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Kawai S, Takeshima N, Hayasaka Y, Notsu A, Yamazaki M, Kawabata T, Yamazaki K, Mori K, Yasui H. Comparison of irinotecan and oxaliplatin as the first-line therapies for metastatic colorectal cancer: a meta-analysis. BMC Cancer 2021; 21:116. [PMID: 33541293 PMCID: PMC7863255 DOI: 10.1186/s12885-021-07823-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 01/20/2021] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Irinotecan (IRI) and oxaliplatin (Ox) are standard therapeutic agents of the first-line treatments for metastatic colorectal cancer (mCRC). Previous meta-analyses of randomized controlled trials (RCTs) showed that treatment with Ox-based compared with IRI-based regimens was associated with better overall survival (OS). However, these reports did not include trials of molecular targeting agents and did not take methods for the administration of concomitant drugs, such as bolus or continuous infusion of 5-fluorouracil, into account. A systematic literature review was performed to compare the efficacy and toxicity profiles between IRI- and Ox-based regimens as the first-line treatments for mCRC. METHODS This meta-analysis used data from the Cochrane Central Register of Controlled Trials, PubMed, and SCOPUS. The primary endpoint was OS, and the secondary endpoints were progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs). RESULTS Nineteen trials involving 4571 patients were included in the analysis. No statistically significant difference was observed between the two groups in terms of OS, PFS, and ORR. There was no significant heterogeneity. Regarding ≥ grade 3 AEs, IRI-based regimens were associated with a high incidence of leukopenia, febrile neutropenia, and diarrhea. Moreover, there was a high incidence of thrombocytopenia and peripheral sensory neuropathy in patients who received Ox-based regimens. In a subgroup analysis, IRI combined with bevacizumab was correlated with a better PFS (HR = 0.90, 95% CI = 0.82-0.98, P = 0.02), but not with OS (pooled HR = 0.91, 95% CI = 0.80-1.03, P = 0.15). CONCLUSION Although the safety profiles of IRI- and Ox-based regimens varied, their efficacy did not significantly differ. The combination of anti-VEGF antibody and IRI was associated with better PFS compared with anti-VEGF antibody and Ox. Both regimens could be used as the first-line treatments for mCRC with consideration of the patients' condition or toxicity profiles.
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Affiliation(s)
- Sadayuki Kawai
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi, Sunto-gun, Shizuoka, 411-8777, Japan.
- Department of Medical Oncology, Shizuoka General Hospital, 4-27-1 Kita ando, Aoi-ku, Shizuoka City, 420-8527, Japan.
| | - Nozomi Takeshima
- Department of Psychiatry, Kitabayashi Hospital, 7-58 Nakamura-cho, Nakamura-ku, Nagoya, Aichi, 453-0053, Japan
| | - Yu Hayasaka
- Department of Psychiatry, Tsukuba Psychosomatics Clinic, 5-12-4, Kenkyu-gakuen, Tsukuba, Ibaraki, 305-0817, Japan
| | - Akifumi Notsu
- Clinical Research Center, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi, Sunto-gun, Shizuoka, 411-8777, Japan
| | - Mutsumi Yamazaki
- Information Management Office, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi, Sunto-gun, Shizuoka, 411-8777, Japan
| | - Takanori Kawabata
- Clinical Research Center, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi, Sunto-gun, Shizuoka, 411-8777, Japan
| | - Kentaro Yamazaki
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi, Sunto-gun, Shizuoka, 411-8777, Japan
| | - Keita Mori
- Clinical Research Center, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi, Sunto-gun, Shizuoka, 411-8777, Japan
| | - Hirofumi Yasui
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi, Sunto-gun, Shizuoka, 411-8777, Japan
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13
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Managing the Primary Tumor in Patients With Incurable Metastatic Rectal Cancer. Dis Colon Rectum 2021; 64:5-6. [PMID: 33306523 DOI: 10.1097/dcr.0000000000001833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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14
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Delos Santos S, Udayakumar S, Nguyen A, Ko YJ, Berry S, Doherty M, Chan KKW. A systematic review and network meta-analysis of second-line therapy in hepatocellular carcinoma. Curr Oncol 2020; 27:300-306. [PMID: 33380861 PMCID: PMC7755448 DOI: 10.3747/co.27.6583] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Background In patients with advanced hepatocellular carcinoma (hcc) following sorafenib failure, it is unclear which treatment is most efficacious, as treatments in the second-line setting have not been directly compared and no standard therapy exists. This systematic review and network meta-analysis (nma) aimed to compare the clinical benefits and toxicities of these treatments. Methods A systematic review of randomized controlled trials (rcts) was conducted to identify phase iii rcts in advanced hcc following sorafenib failure. Baseline characteristics and outcomes of placebo were examined for heterogeneity. Primary outcomes of interest were extracted for results, including overall survival (os), progression-free survival (pfs), objective response rate (orr), grade 3/4 toxicities, and subgroups. An nma was conducted to compare both drugs through the intermediate placebo. Comparisons were expressed as hazard ratios (hrs) for os and pfs, and as risk difference (rd) for orr and toxicities. Subgroup analyses for os and pfs were also performed. Results Two rcts were identified (1280 patients) and compared through an indirect network; celestial (cabozantinib vs. placebo) and resorce (regorafenib vs. placebo). Baseline characteristics of patients in both trials were similar. Both trials also had similar placebo outcomes. Cabozantinib, compared with regorafenib, showed similar os [hazard ratio (hr): 1.21; 95% confidence interval (ci): 0.90 to 1.62], pfs (hr: 1.02; 95% ci: 0.78 to 1.34) and orr (-3.0%; 95% ci: -7.6% to 1.7%). Both treatments showed similar toxicities, but there were marginally higher risks of grade 3/4 hand-foot syndrome (5%; 95% ci: 0.1% to 9.8%), diarrhea (4.8%; 95% ci: 1.1% to 8.5%), and anorexia (4.4%; 95% ci: 0.8% to 8.0%) for cabozantinib. Subgroup results for os and pfs were consistent with overall results. Conclusions Overall, this nma determined that cabozantinib and regorafenib have similar clinical benefits and toxicities for second-line hcc.
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Affiliation(s)
- S Delos Santos
- Sunnybrook Research Institute, University of Toronto, Toronto, ON
| | - S Udayakumar
- Sunnybrook Research Institute, University of Toronto, Toronto, ON
| | - A Nguyen
- Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON
| | - Y J Ko
- Sunnybrook Research Institute, University of Toronto, Toronto, ON
- Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON
- Department of Medicine, University of Toronto, Toronto, ON
| | - S Berry
- Sunnybrook Research Institute, University of Toronto, Toronto, ON
- Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON
- Department of Medicine, University of Toronto, Toronto, ON
| | - M Doherty
- Sunnybrook Research Institute, University of Toronto, Toronto, ON
- Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON
- Department of Medicine, University of Toronto, Toronto, ON
| | - K K W Chan
- Sunnybrook Research Institute, University of Toronto, Toronto, ON
- Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON
- Department of Medicine, University of Toronto, Toronto, ON
- Canadian Centre for Applied Research in Cancer Control, Toronto, ON
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15
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Bolhuis K, Kos M, van Oijen MGH, Swijnenburg RJ, Punt CJA. Conversion strategies with chemotherapy plus targeted agents for colorectal cancer liver-only metastases: A systematic review. Eur J Cancer 2020; 141:225-238. [PMID: 33189037 DOI: 10.1016/j.ejca.2020.09.037] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 09/07/2020] [Accepted: 09/27/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND There is no consensus on the optimal systemic conversion therapy in patients with unresectable colorectal cancer liver-only metastases (CRLM) to achieve a complete resection. Interpretation of trials is complicated by heterogeneity of patients caused by emerging prognostic and predictive characteristics, such as RAS/BRAF mutation status, lack of consensus on unresectability criteria and lack of data on clinical outcome of secondary resections. A systematic review was performed of characteristics of study populations and methodology of trials regarding patients with initially unresectable colorectal cancer liver-only metastases. METHODS Phase II/III randomised trials, published after 2008, regarding first-line systemic conversion therapy in patients or subgroups of patients with CRLM were included. Data on secondary resection outcomes were collected. RESULTS Overall, 20 trials were included for analysis: seven prospective trials in patients with unresectable CRLM and 13 trials in the overall population of unresectable metastatic colorectal cancer (mCRC) with retrospective subgroup analysis of CRLM patients. Fourteen trials did not provide unresectability criteria at baseline, and criteria differed among the remaining studies. Trials and study populations were heterogeneous in prognostic/predictive factors, use of primary end-points, and reporting on long-term clinical outcomes. R0-resection rates in CRLM patients varied between CRLM studies and mCRC studies, with rates of 22-57% and 11-38%, respectively. CONCLUSIONS Cross-study comparison of (subgroups of) studies regarding first-line systemic treatment in patients with unresectable CRLM is hampered by heterogeneity in study populations, trial designs, use of (K)RAS/BRAF mutational tumour status, and differences/absence of unresectability criteria. No optimal conversion systemic regimen can be selected from available data. Prospective studies with well-defined criteria of these issues are warranted.
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Affiliation(s)
- Karen Bolhuis
- Amsterdam UMC, University of Amsterdam, Department of Medical Oncology, Amsterdam, the Netherlands.
| | - Milan Kos
- Amsterdam UMC, University of Amsterdam, Department of Medical Oncology, Amsterdam, the Netherlands
| | - Martijn G H van Oijen
- Amsterdam UMC, University of Amsterdam, Department of Medical Oncology, Amsterdam, the Netherlands
| | - Rutger-Jan Swijnenburg
- Amsterdam UMC, University of Amsterdam, Department of Surgery, Amsterdam, the Netherlands
| | - Cornelis J A Punt
- Amsterdam UMC, University of Amsterdam, Department of Medical Oncology, Amsterdam, the Netherlands; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, the Netherlands
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16
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Simillis C, Singh HKSI, Afxentiou T, Mills S, Warren OJ, Smith JJ, Riddle P, Adamina M, Cunningham D, Tekkis PP. Postoperative chemotherapy improves survival in patients with resected high-risk Stage II colorectal cancer: results of a systematic review and meta-analysis. Colorectal Dis 2020; 22:1231-1244. [PMID: 31999888 DOI: 10.1111/codi.14994] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Accepted: 01/07/2020] [Indexed: 02/08/2023]
Abstract
AIM The aim was to assess the benefit of adjuvant chemotherapy in high-risk Stage II colorectal cancer. METHOD A systematic literature review and meta-analysis was performed comparing survival in patients with resected Stage II colorectal cancer and high-risk features having postoperative chemotherapy vs no chemotherapy. RESULTS Of 1031 articles screened, 29 were included, reporting on 183 749 participants. Adjuvant chemotherapy significantly improved overall survival [hazard ratio (HR) 0.61, P < 0.0001], disease-specific survival (HR = 0.73, P = 0.05) and disease-free survival (HR = 0.59, P < 0.0001) compared to no chemotherapy. Adjuvant chemotherapy significantly increased 5-year overall survival (OR = 0.53, P = 0.0008) and 5-year disease-free survival (OR = 0.50, P = 0.001). Overall survival and disease-free survival remained significantly prolonged during subgroup analysis of studies published from 2015 onwards (HR = 0.60, P < 0.0001; HR = 0.65, P = 0.0001; respectively), in patients with two or more high-risk features (HR = 0.59, P = 0.0001; HR = 0.70, P = 0.03; respectively) and in colon cancer (HR = 0.61, P < 0.0001; HR = 0.51, P = 0.0001; respectively). Overall survival, disease-specific survival and disease-free survival during subgroup analysis of individual high-risk features were T4 tumour (HR = 0.58, P < 0.0001; HR = 0.50, P = 0.003; HR = 0.75, P = 0.05), < 12 lymph nodes harvested (HR = 0.67, P = 0.0002; HR = 0.80, P = 0.17; HR = 0.72, P = 0.02), poor differentiation (HR = 0.84, P = 0.35; HR = 0.85, P = 0.23; HR = 0.61, P = 0.41), lymphovascular or perineural invasion (HR = 0.55, P = 0.05; HR = 0.59, P = 0.11; HR = 0.76, P = 0.05) and emergency surgery (HR = 0.60, P = 0.02; HR = 0.68, P = 0.19). CONCLUSION Adjuvant chemotherapy in high-risk Stage II colorectal cancer results in a modest survival improvement and should be considered on an individual patient basis. Due to potential heterogeneity and selection bias of the included studies, and lack of separate rectal cancer data, further large randomized trials with predefined inclusion criteria and standardized chemotherapy regimens are required.
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Affiliation(s)
- C Simillis
- Department of Colorectal Surgery, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK.,Department of Surgery and Cancer, Imperial College, London, UK
| | - H K S I Singh
- Department of Colorectal Surgery, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK
| | - T Afxentiou
- Department of Clinical Oncology, Imperial College Healthcare NHS Trust, London, UK
| | - S Mills
- Department of Colorectal Surgery, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK.,Department of Surgery and Cancer, Imperial College, London, UK
| | - O J Warren
- Department of Colorectal Surgery, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK.,Department of Surgery and Cancer, Imperial College, London, UK
| | - J J Smith
- Department of Colorectal Surgery, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK.,Department of Surgery and Cancer, Imperial College, London, UK
| | - P Riddle
- Department of Clinical Oncology, Imperial College Healthcare NHS Trust, London, UK
| | - M Adamina
- Department of Surgery, Cantonal Hospital Winterthur, Winterthur, Switzerland
| | - D Cunningham
- Gastrointestinal Unit, The Royal Marsden Hospital, London, UK
| | - P P Tekkis
- Department of Colorectal Surgery, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK.,Department of Surgery and Cancer, Imperial College, London, UK.,Gastrointestinal Unit, The Royal Marsden Hospital, London, UK
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17
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Kuchel A, Ahern E, Collins S, Whitehall V, Okano S, Pelecanos A, Wyld D, Eastgate M, Burge M. Trends in epidemiology, treatment and molecular testing of metastatic colorectal cancer in a real-world multi-institution cohort study. Asia Pac J Clin Oncol 2020; 17:84-93. [PMID: 32978897 DOI: 10.1111/ajco.13420] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Accepted: 06/15/2020] [Indexed: 01/08/2023]
Abstract
AIM Colorectal cancer (CRC) is the third most common cancer in Australia, and survival after diagnosis of metastatic disease is improving. Our aim was to assess trends in epidemiology, treatment, molecular testing and survival in patients with metastatic CRC (mCRC). METHODS Clinical data from February 2013 to December 2018 was recorded in a prospective, observational, multicenter cohort study conducted in Queensland, Australia, examining clinical and molecular biomarkers in cases of mCRC. RESULTS A total of 159 patients who had metastasis diagnosed after February 2013 were included in survival analysis. Median age at diagnosis was 63.9 years, but 29% had early-onset disease (diagnosis aged <50 years). Median overall survival was 2.5 years (95% confidence interval [CI], 2.2-3.0) for the 159 patients included in survival analysis. Independent factors correlated with poor prognosis included right-sided primary tumor, neutrophil-lymphocyte ratio >5, increased alkaline phosphatase level (ALP) and an increasing number of sites of metastatic disease. In contrast, metastasectomy was associated with improved overall survival (adjusted HR = 0.29' 95% CI, 0.16-0.54), with similar survival between patients who had liver and non-liver metastasectomy sites. Half (10/20) of the BRAF mutant CRC were also microsatellite unstable. The proportion of detected mutations amongst tested samples increased over time for Kirsten Rat Sarcoma (KRAS; OR [per year] = 1.19; 95% CI, 1.01-1.39). Concurrently, the methods of molecular genetics testing employed in routine clinical practice changed towards the adoption of next-generation sequencing. CONCLUSIONS Metastasectomy in mCRC may be beneficial regardless of the anatomical site of metastasis. The adoption of next-generation sequencing techniques for molecular genetics testing coincided with a slightly increased rate of detection of KRAS and BRAF mutations, potentially reflecting greater test sensitivity. Further translational research is required in mCRC to define novel targets for treatment.
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Affiliation(s)
- Anna Kuchel
- Department of Medical Oncology, Cancer Care Services, The Royal Brisbane and Women's Hospital, Herston, Australia.,School of Medicine, University of Queensland, Herston, Australia.,Immunology in Cancer and Infection, Queensland Institute of Medical Research Berghofer, Herston, Australia
| | - Elizabeth Ahern
- Department of Medical Oncology, Cancer Care Services, The Royal Brisbane and Women's Hospital, Herston, Australia.,School of Medicine, University of Queensland, Herston, Australia.,Immunology in Cancer and Infection, Queensland Institute of Medical Research Berghofer, Herston, Australia
| | - Stephanie Collins
- Department of Medical Oncology, Cancer Care Services, The Royal Brisbane and Women's Hospital, Herston, Australia.,School of Medicine, University of Queensland, Herston, Australia
| | - Vicki Whitehall
- School of Medicine, University of Queensland, Herston, Australia.,Conjoint Gastroenterology Laboratory, Queensland Institute of Medical Research Berghofer, Herston, Australia.,Conjoint Internal Medicine Laboratory, Pathology Queensland, Queensland Health, Brisbane, Australia
| | - Satomi Okano
- Statistics Unit, Queensland Institute of Medical Research Berghofer, Herston, Australia
| | - Anita Pelecanos
- Statistics Unit, Queensland Institute of Medical Research Berghofer, Herston, Australia
| | - David Wyld
- Department of Medical Oncology, Cancer Care Services, The Royal Brisbane and Women's Hospital, Herston, Australia.,School of Medicine, University of Queensland, Herston, Australia.,Immunology in Cancer and Infection, Queensland Institute of Medical Research Berghofer, Herston, Australia
| | - Melissa Eastgate
- Department of Medical Oncology, Cancer Care Services, The Royal Brisbane and Women's Hospital, Herston, Australia.,School of Medicine, University of Queensland, Herston, Australia.,Conjoint Gastroenterology Laboratory, Queensland Institute of Medical Research Berghofer, Herston, Australia
| | - Matthew Burge
- Department of Medical Oncology, Cancer Care Services, The Royal Brisbane and Women's Hospital, Herston, Australia.,School of Medicine, University of Queensland, Herston, Australia.,Conjoint Gastroenterology Laboratory, Queensland Institute of Medical Research Berghofer, Herston, Australia.,Department of Medical Oncology, The Prince Charles Hospital, Chermside, Australia
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18
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Belardinilli F, Capalbo C, Malapelle U, Pisapia P, Raimondo D, Milanetti E, Yasaman M, Liccardi C, Paci P, Sibilio P, Pepe F, Bonfiglio C, Mezi S, Magri V, Coppa A, Nicolussi A, Gradilone A, Petroni M, Di Giulio S, Fabretti F, Infante P, Coni S, Canettieri G, Troncone G, Giannini G. Clinical Multigene Panel Sequencing Identifies Distinct Mutational Association Patterns in Metastatic Colorectal Cancer. Front Oncol 2020; 10:560. [PMID: 32457828 PMCID: PMC7221020 DOI: 10.3389/fonc.2020.00560] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Accepted: 03/27/2020] [Indexed: 12/12/2022] Open
Abstract
Extensive molecular characterization of human colorectal cancer (CRC) via Next Generation Sequencing (NGS) indicated that genetic or epigenetic dysregulation of a relevant, but limited, number of molecular pathways typically occurs in this tumor. The molecular picture of the disease is significantly complicated by the frequent occurrence of individually rare genetic aberrations, which expand tumor heterogeneity. Inter- and intratumor molecular heterogeneity is very likely responsible for the remarkable individual variability in the response to conventional and target-driven first-line therapies, in metastatic CRC (mCRC) patients, whose median overall survival remains unsatisfactory. Implementation of an extensive molecular characterization of mCRC in the clinical routine does not yet appear feasible on a large scale, while multigene panel sequencing of most commonly mutated oncogene/oncosuppressor hotspots is more easily achievable. Here, we report that clinical multigene panel sequencing performed for anti-EGFR therapy predictive purposes in 639 formalin-fixed paraffin-embedded (FFPE) mCRC specimens revealed previously unknown pairwise mutation associations and a high proportion of cases carrying actionable gene mutations. Most importantly, a simple principal component analysis directed the delineation of a new molecular stratification of mCRC patients in eight groups characterized by non-random, specific mutational association patterns (MAPs), aggregating samples with similar biology. These data were validated on a The Cancer Genome Atlas (TCGA) CRC dataset. The proposed stratification may provide great opportunities to direct more informed therapeutic decisions in the majority of mCRC cases.
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Affiliation(s)
| | - Carlo Capalbo
- Department of Molecular Medicine, University La Sapienza, Rome, Italy
| | | | - Pasquale Pisapia
- Department of Public Health, University Federico II, Naples, Italy
| | - Domenico Raimondo
- Department of Molecular Medicine, University La Sapienza, Rome, Italy
| | | | - Mahdavian Yasaman
- Department of Molecular Medicine, University La Sapienza, Rome, Italy
| | - Carlotta Liccardi
- Department of Molecular Medicine, University La Sapienza, Rome, Italy
| | - Paola Paci
- Institute for System Analysis and Computer Science "Antonio Ruberti", National Research Council, Rome, Italy
| | - Pasquale Sibilio
- Institute for System Analysis and Computer Science "Antonio Ruberti", National Research Council, Rome, Italy
| | - Francesco Pepe
- Department of Public Health, University Federico II, Naples, Italy
| | - Caterina Bonfiglio
- National Institute of Gastroenterology-Research Hospital, IRCCS "S. de Bellis", Bari, Italy
| | - Silvia Mezi
- Department of Radiological Oncological and Pathological Sciences, University La Sapienza, Rome, Italy
| | - Valentina Magri
- Department of Surgery Pietro Valdoni, Faculty of Medicine and Dentistry, Sapienza University of Rome, Rome, Italy
| | - Anna Coppa
- Department of Experimental Medicine, University La Sapienza, Rome, Italy
| | - Arianna Nicolussi
- Department of Experimental Medicine, University La Sapienza, Rome, Italy
| | - Angela Gradilone
- Department of Molecular Medicine, University La Sapienza, Rome, Italy
| | - Marialaura Petroni
- Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy
| | - Stefano Di Giulio
- Department of Molecular Medicine, University La Sapienza, Rome, Italy
| | | | - Paola Infante
- Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy
| | - Sonia Coni
- Department of Molecular Medicine, University La Sapienza, Rome, Italy
| | - Gianluca Canettieri
- Department of Molecular Medicine, University La Sapienza, Rome, Italy.,Pasteur Institute-Cenci Bolognetti Foundation, Rome, Italy
| | | | - Giuseppe Giannini
- Department of Molecular Medicine, University La Sapienza, Rome, Italy.,Pasteur Institute-Cenci Bolognetti Foundation, Rome, Italy
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19
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Ravn S, Christiansen CF, Hagemann-Madsen RH, Verwaal VJ, Iversen LH. The Validity of Registered Synchronous Peritoneal Metastases from Colorectal Cancer in the Danish Medical Registries. Clin Epidemiol 2020; 12:333-343. [PMID: 32273772 PMCID: PMC7108706 DOI: 10.2147/clep.s238193] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Accepted: 02/24/2020] [Indexed: 12/16/2022] Open
Abstract
Introduction Treatment options for peritoneal metastases (PM) from colorectal cancer (CRC) have increased, their efficiency should be monitored. For this purpose, register-based data on PM can be used, if valid. Purpose We aimed to evaluate the completeness and positive predictive value (PPV) of synchronous peritoneal metastases (S-PM) registered among CRC patients in the Danish National Patient Register (DNPR) and/or the Danish National Pathology Register (the DNPatR) using the Danish Colorectal Cancer Group database (DCCG) as a reference. Patients and Methods We identified Danish patients with newly diagnosed primary CRC in the DCCG during 2014–2015. S-PM were routinely registered in the DCCG. We excluded patients with non-CRC cancers and identified S-PM using all three registries. We estimated the completeness and the PPV of registered S-PM in the DNPR, the DNPatR and the DNPR and/or the DNPatR (DNPR/DNPatR) in combination using the DCCG as the reference. We stratified by age, gender, WHO performance status, tumour location and distant metastases to liver and/or lungs. Results We identified 9142 patients with CRC in DCCG. In DCCG, 366 patients were registered with S-PM, among whom 213 in DCCG only, whereas 153 in DCCG and in at least one of DNPR and/or DNPatR. In DNPR/DNPatR, S-PM was registered with a completeness of 42% [95% CI: 37–47] and a PPV of 60% [95% CI: 54–66]. In the DNPR only, the completeness was 32% [95% CI: 27–37] and the PPV 57% [95% CI: 50–64]. The completeness in the DNPatR was 19% [95% CI: 15–23] and the PPV was 76% [95% CI: 68–85]. In the DNPR/DNPatR patients aged <60 years (57% [95% CI: 46–69]), patients with WHO performance status 0 (46% [95% CI: 37–54]) and patients with no distant metastases (58% [95% CI: 50–65]) were registered with a higher completeness. Conclusion Our algorithm demonstrates that the DNPR/DNPatR captures less than half of CRC patients with S-PM. Potential candidates for curative treatment options are registered with a higher completeness. Clinicians should be encouraged to register the presence of S-PM to increase the validity of register-based S-PM data.
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Affiliation(s)
- Sissel Ravn
- Department of Surgery, Aarhus University Hospital, Aarhus, Denmark
| | | | | | - Victor J Verwaal
- Department of Surgery, Aarhus University Hospital, Aarhus, Denmark
| | - Lene H Iversen
- Department of Surgery, Aarhus University Hospital, Aarhus, Denmark.,Danish Colorectal Cancer Group (DCCG), Copenhagen, Denmark
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20
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New rising entities in cancer of unknown primary: Is there a real therapeutic benefit? Crit Rev Oncol Hematol 2020; 147:102882. [DOI: 10.1016/j.critrevonc.2020.102882] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2019] [Revised: 12/04/2019] [Accepted: 01/17/2020] [Indexed: 12/11/2022] Open
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21
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Otoukesh S, Salhotra A, Marcucci G, Forman SJ, Pullarkat V, Aldoss I. The feasibility of venetoclax and decitabine in therapy-related acute myeloid leukemia with concurrent advanced non-hematological malignancies. Leuk Res 2019; 84:106196. [PMID: 31377457 DOI: 10.1016/j.leukres.2019.106196] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Accepted: 07/27/2019] [Indexed: 11/19/2022]
MESH Headings
- Antineoplastic Combined Chemotherapy Protocols/adverse effects
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Bridged Bicyclo Compounds, Heterocyclic/administration & dosage
- Decitabine/administration & dosage
- Humans
- Leukemia, Myeloid, Acute/complications
- Leukemia, Myeloid, Acute/diagnosis
- Leukemia, Myeloid, Acute/drug therapy
- Leukemia, Myeloid, Acute/mortality
- Neoplasms/complications
- Neoplasms/diagnosis
- Neoplasms/drug therapy
- Neoplasms/mortality
- Neoplasms, Second Primary/diagnosis
- Neoplasms, Second Primary/drug therapy
- Neoplasms, Second Primary/mortality
- Sulfonamides/administration & dosage
- Treatment Outcome
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Affiliation(s)
- Salman Otoukesh
- Department of Hematology and Hematopoietic Cell Transplantation, Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA, United States
| | - Amandeep Salhotra
- Department of Hematology and Hematopoietic Cell Transplantation, Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA, United States
| | - Guido Marcucci
- Department of Hematology and Hematopoietic Cell Transplantation, Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA, United States
| | - Stephen J Forman
- Department of Hematology and Hematopoietic Cell Transplantation, Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA, United States
| | - Vinod Pullarkat
- Department of Hematology and Hematopoietic Cell Transplantation, Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA, United States
| | - Ibrahim Aldoss
- Department of Hematology and Hematopoietic Cell Transplantation, Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA, United States.
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22
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Zhang D, Wu JR, Duan XJ, Wang KH, Zhao Y, Ni MW, Liu SY, Zhang XM, Zhang B. A Bayesian Network Meta-Analysis for Identifying the Optimal Taxane-Based Chemotherapy Regimens for Treating Gastric Cancer. Front Pharmacol 2019; 10:717. [PMID: 31333452 PMCID: PMC6624233 DOI: 10.3389/fphar.2019.00717] [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] [Received: 06/04/2018] [Accepted: 06/05/2019] [Indexed: 01/30/2023] Open
Abstract
Background: Several taxane-based chemotherapy regimens are effective in the treatment of gastric cancer; nevertheless, their comparative efficacy and safety remain disputed. This network meta-analysis (NMA) was designed to compare the efficacy and safety of different taxane-based chemotherapy regimens against gastric cancer. Methods: A comprehensive search was conducted to identify all relevant randomized controlled trials (RCTs) in multiple electronic databases. A Bayesian NMA was performed to combine the direct and indirect evidence and estimate the comparative efficacy and safety of different taxane-based chemotherapy regimens simultaneously by utilizing WinBUGS 1.4.3 and Stata 13.1 software. The efficacy outcomes included overall survival rate (OS), progression-free survival (PFS), and overall response rate (ORR), and the safety outcomes were adverse reactions (ADRs), namely, neutropenia, leucopenia, vomiting, and fatigue. Results: A total of 37 RCTs were identified involving 7,178 patients with gastric cancer, and 10 taxane-based chemotherapy regimens (RT, T, TC, TCF, TF, TO, TOF, mTCF, mTF, and mTOF) were collected in gastric cancer therapy. According to the results of cluster analysis, compared with other taxane-based chemotherapy regimens, the regimens of TOF, mTCF, and TF were associated with the most favorable clinical efficacy in improving OS, PFS, and ORR. On the other hand, the regimens of T and mTF had the potential to be the most tolerable and acceptable therapeutic alternative in terms of ADRs. Conclusions: The current NMA provides the evidence that the combination of taxanes (paclitaxel or docetaxel) and fluorouracil is associated with the most preferable and beneficial option for patients with gastric cancer, although additional results from multicenter trials and high-quality studies will be pivotal for supporting our findings.
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Affiliation(s)
- Dan Zhang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Jia-Rui Wu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Xiao-Jiao Duan
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Kai-Huan Wang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Yi Zhao
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Meng-Wei Ni
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Shu-Yu Liu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Xiao-Meng Zhang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Bing Zhang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
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Simillis C, Kalakouti E, Afxentiou T, Kontovounisios C, Smith JJ, Cunningham D, Adamina M, Tekkis PP. Primary Tumor Resection in Patients with Incurable Localized or Metastatic Colorectal Cancer: A Systematic Review and Meta-analysis. World J Surg 2019; 43:1829-1840. [DOI: 10.1007/s00268-019-04984-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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24
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Capalbo C, Belardinilli F, Raimondo D, Milanetti E, Malapelle U, Pisapia P, Magri V, Prete A, Pecorari S, Colella M, Coppa A, Bonfiglio C, Nicolussi A, Valentini V, Tessitore A, Cardinali B, Petroni M, Infante P, Santoni M, Filetti M, Colicchia V, Paci P, Mezi S, Longo F, Cortesi E, Marchetti P, Troncone G, Bellavia D, Canettieri G, Giannini G. A Simplified Genomic Profiling Approach Predicts Outcome in Metastatic Colorectal Cancer. Cancers (Basel) 2019; 11:cancers11020147. [PMID: 30691222 PMCID: PMC6406354 DOI: 10.3390/cancers11020147] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2018] [Revised: 01/19/2019] [Accepted: 01/22/2019] [Indexed: 12/22/2022] Open
Abstract
The response of metastatic colorectal cancer (mCRC) to the first-line conventional combination therapy is highly variable, reflecting the elevated heterogeneity of the disease. The genetic alterations underlying this heterogeneity have been thoroughly characterized through omic approaches requiring elevated efforts and costs. In order to translate the knowledge of CRC molecular heterogeneity into a practical clinical approach, we utilized a simplified Next Generation Sequencing (NGS) based platform to screen a cohort of 77 patients treated with first-line conventional therapy. Samples were sequenced using a panel of hotspots and targeted regions of 22 genes commonly involved in CRC. This revealed 51 patients carrying actionable gene mutations, 22 of which carried druggable alterations. These mutations were frequently associated with additional genetic alterations. To take into account this molecular complexity and assisted by an unbiased bioinformatic analysis, we defined three subgroups of patients carrying distinct molecular patterns. We demonstrated these three molecular subgroups are associated with a different response to first-line conventional combination therapies. The best outcome was achieved in patients exclusively carrying mutations on TP53 and/or RAS genes. By contrast, in patients carrying mutations in any of the other genes, alone or associated with mutations of TP53/RAS, the expected response is much worse compared to patients with exclusive TP53/RAS mutations. Additionally, our data indicate that the standard approach has limited efficacy in patients without any mutations in the genes included in the panel. In conclusion, we identified a reliable and easy-to-use approach for a simplified molecular-based stratification of mCRC patients that predicts the efficacy of the first-line conventional combination therapy.
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Affiliation(s)
- Carlo Capalbo
- Department of Molecular Medicine, University La Sapienza, 00161 Rome, Italy.
- Department of Medical Oncology Sant' Andrea Hospital, I-00189 Rome, Italy.
| | | | - Domenico Raimondo
- Department of Molecular Medicine, University La Sapienza, 00161 Rome, Italy.
| | | | - Umberto Malapelle
- Department of Public Health, University Federico II, 80131 Naples, Italy.
| | - Pasquale Pisapia
- Department of Public Health, University Federico II, 80131 Naples, Italy.
| | - Valentina Magri
- Department of Radiological Oncological and Pathological Sciences, University La Sapienza, 00161 Rome, Italy.
| | - Alessandra Prete
- Department of Radiological Oncological and Pathological Sciences, University La Sapienza, 00161 Rome, Italy.
| | - Silvia Pecorari
- Department of Radiological Oncological and Pathological Sciences, University La Sapienza, 00161 Rome, Italy.
| | | | - Anna Coppa
- Department of Experimental Medicine, University La Sapienza, 00161 Rome, Italy.
| | - Caterina Bonfiglio
- National Institute of Gastroenterology-Research Hospital, IRCCS "S. de Bellis", Castellana Grotte, 70013 Bari, Italy.
| | - Arianna Nicolussi
- Department of Experimental Medicine, University La Sapienza, 00161 Rome, Italy.
| | - Virginia Valentini
- Department of Molecular Medicine, University La Sapienza, 00161 Rome, Italy.
| | - Alessandra Tessitore
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
| | - Beatrice Cardinali
- Institute of Cell Biology and Neurobiology, National Research Council, Campus A. Buzzati-Traverso, 00015 Monterotondo Scalo, Italy.
| | - Marialaura Petroni
- Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, 00161 Rome, Italy.
| | - Paola Infante
- Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, 00161 Rome, Italy.
| | - Matteo Santoni
- Oncology Unit, Macerata Hospital, 62012 Macerata, Italy.
| | - Marco Filetti
- Department of Medical Oncology Sant' Andrea Hospital, I-00189 Rome, Italy.
| | - Valeria Colicchia
- Department of Molecular Medicine, University La Sapienza, 00161 Rome, Italy.
| | - Paola Paci
- Institute for Systems Analysis and Computer Science "Antonio Ruberti", National Research Council, 00185 Rome, Italy.
| | - Silvia Mezi
- Department of Radiological Oncological and Pathological Sciences, University La Sapienza, 00161 Rome, Italy.
| | - Flavia Longo
- Department of Radiological Oncological and Pathological Sciences, University La Sapienza, 00161 Rome, Italy.
| | - Enrico Cortesi
- Department of Radiological Oncological and Pathological Sciences, University La Sapienza, 00161 Rome, Italy.
| | - Paolo Marchetti
- Department of Medical Oncology Sant' Andrea Hospital, I-00189 Rome, Italy.
| | - Giancarlo Troncone
- Department of Public Health, University Federico II, 80131 Naples, Italy.
| | - Diana Bellavia
- Department of Molecular Medicine, University La Sapienza, 00161 Rome, Italy.
| | - Gianluca Canettieri
- Department of Molecular Medicine, University La Sapienza, 00161 Rome, Italy.
- Pasteur Institute-Cenci Bolognetti Foundation, 00161 Rome, Italy.
| | - Giuseppe Giannini
- Department of Molecular Medicine, University La Sapienza, 00161 Rome, Italy.
- Pasteur Institute-Cenci Bolognetti Foundation, 00161 Rome, Italy.
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Abstract
Summary
The best effective dose of a chemotherapy is defined using the maximum tolerated dose (MTD) of toxicity. It is possible that the toxicity of a dose may increase when the dose-response curve is not monotonic. In the case of metronomic chemotherapy (MC) a 1/10th level of MC dose is considered as a targeted dose of therapy and is safer in terms of toxicity levels. The objective of this study is to develop an algorithm based on the dose response model of MC to evaluate the best effective dose based on the molecular target agent. The molecular target agent is defined as the optimal biological dose achieved by the best effective dose, as the lowest dose with the highest rate of safety and efficacy. The first proposed design is parametric and assumes a logistic dose-efficacy curve for dose determination, and the second design uses quadratic regression to identify the optimal biological dose. We conducted extensive simulation studies to investigate the operating characteristics of the proposed designs. Simulation studies provide a possible way to decide on the best effective dose of MC to be considered in further phases through the finding of the optimal biological dose. The proposed design is assumed, with the threshold value of optimum biological dose (OBD), to detect the best dose of MC. This consistent design with specific dose response models can be recommended for practice.
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26
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Chan KKW, Saluja R, Delos Santos K, Lien K, Shah K, Cramarossa G, Zhu X, Wong RKS. Neoadjuvant treatments for locally advanced, resectable esophageal cancer: A network meta-analysis. Int J Cancer 2018; 143:430-437. [PMID: 29441562 DOI: 10.1002/ijc.31312] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Revised: 12/06/2017] [Accepted: 01/09/2018] [Indexed: 02/06/2023]
Abstract
The relative survival benefits and postoperative mortality among the different types of neoadjuvant treatments (such as chemotherapy only, radiotherapy only or chemoradiotherapy) for esophageal cancer patients are not well established. To evaluate the relative efficacy and safety of neoadjuvant therapies in resectable esophageal cancer, a Bayesian network meta-analysis was performed. MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials were searched for publications up to May 2016. ASCO and ASTRO annual meeting abstracts were also searched up to the 2015 conferences. Randomized controlled trials that compared at least two of the following treatments for resectable esophageal cancer were included: surgery alone, surgery preceded by neoadjuvant chemotherapy, neoadjuvant radiotherapy or neoadjuvant chemoradiotherapy. The primary outcome assessed from the trials was overall survival. Thirty-one randomized controlled trials involving 5496 patients were included in the quantitative analysis. The network meta-analysis showed that neoadjuvant chemoradiotherapy improved overall survival when compared to all other treatments including surgery alone (HR 0.75, 95% CR 0.67-0.85), neoadjuvant chemotherapy (HR 0.83. 95% CR 0.70-0.96) and neoadjuvant radiotherapy (HR 0.82, 95% CR 0.67-0.99). However, the risk of postoperative mortality increased when comparing neoadjuvant chemoradiotherapy to either surgery alone (RR 1.46, 95% CR 1.00-2.14) or to neoadjuvant chemotherapy (RR 1.58, 95% CR 1.00-2.49). In conclusion, neoadjuvant chemoradiotherapy improves overall survival but may also increase the risk of postoperative mortality in patients locally advanced resectable esophageal carcinoma.
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Affiliation(s)
- Kelvin K W Chan
- Division of Medical Oncology and Hematology, Sunnybrook Odette Cancer Centre, Toronto, ON, Canada.,Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, ON, Canada.,Canadian Centre for Applied Research in Cancer Control (ARCC), Toronto, ON, Canada
| | - Ronak Saluja
- Division of Medical Oncology and Hematology, Sunnybrook Odette Cancer Centre, Toronto, ON, Canada
| | - Keemo Delos Santos
- Division of Medical Oncology and Hematology, Sunnybrook Odette Cancer Centre, Toronto, ON, Canada
| | - Kelly Lien
- Division of Medical Oncology and Hematology, Sunnybrook Odette Cancer Centre, Toronto, ON, Canada
| | - Keya Shah
- Division of Medical Oncology and Hematology, Sunnybrook Odette Cancer Centre, Toronto, ON, Canada
| | - Gemma Cramarossa
- Division of Medical Oncology and Hematology, Sunnybrook Odette Cancer Centre, Toronto, ON, Canada
| | - Xiaofu Zhu
- Cross Cancer Institute, Edmonton, AB, Canada
| | - Rebecca K S Wong
- Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada
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27
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Qi H, Fan W. Value of ablation therapy in the treatment of lung metastases. Thorac Cancer 2018; 9:199-207. [PMID: 29193688 PMCID: PMC5792733 DOI: 10.1111/1759-7714.12567] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2017] [Accepted: 10/26/2017] [Indexed: 02/06/2023] Open
Abstract
Tumor metastases are the basic biological characteristics of malignant tumors, and the lungs are the second most prominent metastatic organs in which these develop after the liver. Currently, with the rapid development of ablation technology, ablation therapy as a local treatment is playing an increasingly important role in the treatment of lung metastases. Whether alone or in combination with other treatments, ablation therapy has achieved good therapeutic effects for the treatment of partial lung metastases. This article briefly summarizes the results of current and previous ablation treatments for lung metastases, and focuses on the value of ablation therapy for different kinds of lung metastases.
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Affiliation(s)
- Han Qi
- Minimally Invasive Interventional Division, Medical Imaging CenterSun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer MedicineGuangzhouChina
| | - Weijun Fan
- Minimally Invasive Interventional Division, Medical Imaging CenterSun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer MedicineGuangzhouChina
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28
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Shah K, Chan KKW, Ko YJ. A systematic review and network meta-analysis of post-imatinib therapy in advanced gastrointestinal stromal tumour. ACTA ACUST UNITED AC 2017; 24:e531-e539. [PMID: 29270063 DOI: 10.3747/co.24.3463] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Background The standard first-line systemic therapy for advanced gastrointestinal stromal tumour (gist) is imatinib. However, most gists develop imatinib resistance, highlighting the need for new agents in the imatinib-refractory setting. Currently, no randomized studies have directly compared the available post-first-line treatments. Methods In a systematic review, the medline, embase, and central databases, and American Society of Clinical Oncology abstracts to July 2014 were searched to identify randomized controlled trials that included gist patients treated with post-first-line therapies. Hazard ratios (hrs) for progression-free (pfs) and overall survival (os) were extracted. Direct pairwise meta-analyses and indirect comparisons using the Butcher method were performed. Results Four studies were identified for the systematic review. One study showed that sunitinib in the second-line setting (vs. placebo) was associated with improved pfs, but not improved os. Three studies examined the third-line setting (imatinib resumption vs. placebo, regorafenib vs. placebo, nilotinib vs. best supportive care). In the third-line settings, the two placebo-controlled and the non-placebo-controlled trials showed significant heterogeneity (I2 = 98%). Indirect comparisons of imatinib resumption and regorafenib suggested that the hr for pfs was 0.59 (95% confidence interval: 0.31 to 1.12; p = 0.10), trending in favour of regorafenib. Indirect comparisons found that toxicities were higher in the regorafenib group, with a risk difference of 27.8% for any-grade toxicities and 19.5% for grades 3 and 4 toxicities. Conclusions Because a head-to-head study of imatinib resumption compared with regorafenib is unlikely ever to be conducted, our study suggests that, in terms of pfs, regorafenib might be the preferred treatment. However, given the increased toxicity observed with regorafenib, clinicians should interpret that evidence with caution at an individual patient level.
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Affiliation(s)
- K Shah
- Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, ON
| | - K K W Chan
- Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, ON
| | - Y J Ko
- Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, ON
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29
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Wang J, Luo L, Wang D, Guo B, Li J, Yang Z, Tang D. Combination adjuvant chemotherapy with targeted drugs for treatment of colorectal cancer: A network meta-analysis. J Cell Biochem 2017; 119:1521-1537. [PMID: 28771807 DOI: 10.1002/jcb.26312] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Accepted: 08/02/2017] [Indexed: 01/10/2023]
Abstract
Colorectal cancer (CRC) is one of the most fatal diseases in the world. The efficacy of present chemotherapy treatments are limited and the addition of targeted drugs have been put into practice. However, the preferred treatments among adjuvant chemotherapies still remain controversial and uncertain. To evaluate the efficacy of different adjuvant chemotherapies combined with or without targeted drugs to determine the optimal treatment for patients with CRC in clinical practice. PubMed and Embase were searched for eligible articles and only randomized controlled trials (RCTs) were included. R (Version 3.2.5) software was utilized to conduct the Bayesian network meta-analysis (NMA). Outcomes including overall survival (OS) and progression-free survival (PFS) were displayed using hazard ratios. And the rank probabilities of each treatment were evaluated using the surface under cumulative ranking curve. A total of 75 RCTs published after 1997 were included in the data analysis. Overall, FOLFIRI+ cetuximab was found to be the most effective treatment in terms of long-term survival and FOLFOX was the most effective pure chemotherapy treatment. The addition of targeted drugs will greatly improve the efficacy of chemotherapy. Targeted drug cetuximab combined with the chemotherapy regiment FOLFIRI is the preferable treatment for patients with CRC in clinical practice.
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Affiliation(s)
- Jinghui Wang
- Department of Oncological Hematology, First Affiliated Hospital of Guiyang College of TCM, Guiyang, Guizhou, China
| | - Li Luo
- Department of Oncological Hematology, First Affiliated Hospital of Guiyang College of TCM, Guiyang, Guizhou, China
| | - Dingxue Wang
- Department of Oncological Hematology, First Affiliated Hospital of Guiyang College of TCM, Guiyang, Guizhou, China
| | - Bin Guo
- Graduate College of Guiyang College of TCM, Guiyang, Guizhou, China
| | - Jun Li
- College of Basic Medicine of Guiyang College of TCM, Guiyang, Guizhou, China
| | - Zhu Yang
- Deanery of Guiyang College of TCM, Guiyang, Guizhou, China
| | - Dongxin Tang
- Department of Science and Education, First Affiliated Hospital of Guiyang College of TCM, Guiyang, Guizhou, China
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30
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Downs-Canner S, Shuai Y, Ramalingam L, Pingpank JF, Holtzman MP, Zeh HJ, Bartlett DL, Choudry HA. Safety and efficacy of combined resection of colorectal peritoneal and liver metastases. J Surg Res 2017; 219:194-201. [PMID: 29078882 PMCID: PMC5663460 DOI: 10.1016/j.jss.2017.05.126] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Revised: 05/26/2017] [Accepted: 05/30/2017] [Indexed: 12/22/2022]
Abstract
BACKGROUND To determine if a select subgroup of patients with combined liver and peritoneal colorectal metastases would derive oncologic benefit from surgical resection as a component of multimodality treatment. MATERIALS AND METHODS We retrospectively compared 32 patients with combined colorectal peritoneal and liver metastases (CRLM) and 173 patients with peritoneal metastases only (CRPM) undergoing cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion (CRS-HIPEC). Kaplan-Meier survival curves and multivariate Cox-regression models identified prognostic factors affecting survival. RESULTS Major postoperative complications (Clavien-Dindo grades 3-5) occurred in 32% (CRLM) and 17% (CRPM) of patients (P = 0.08). After an estimated median follow-up from surgery of 57 mo, propensity score-adjusted median progression-free survival was 5.1 mo (CRLM) and 7.6 mo (CRPM), whereas median overall survival was 13 mo (CRLM) and 21 mo (CRPM). Multivariate Cox-regression analysis of the CRLM group identified number of liver metastases to be the only independent predictor of poor survival (hazard ratio: 2.3, P = 0.03), with a dramatic decrease in survival in patients with more than three liver metastases. CONCLUSIONS Simultaneous resection of colorectal liver metastases at the time of cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion for peritoneal metastases may be associated with worse survival, especially in patients with more than three liver metastases.
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Affiliation(s)
| | - Yongli Shuai
- The University of Pittsburgh Cancer Institute Biostatistics Facility, Pittsburgh, Pensylvannia
| | - Lekshmi Ramalingam
- Division of Surgical Oncology, University of Pittsburgh, Pittsburgh, Pensylvannia
| | - James F Pingpank
- Division of Surgical Oncology, University of Pittsburgh, Pittsburgh, Pensylvannia
| | - Matthew P Holtzman
- Division of Surgical Oncology, University of Pittsburgh, Pittsburgh, Pensylvannia
| | - Herbert J Zeh
- Division of Surgical Oncology, University of Pittsburgh, Pittsburgh, Pensylvannia
| | - David L Bartlett
- Division of Surgical Oncology, University of Pittsburgh, Pittsburgh, Pensylvannia
| | - Haroon A Choudry
- Division of Surgical Oncology, University of Pittsburgh, Pittsburgh, Pensylvannia.
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Apostolidis L, Schwarz D, Xia A, Weiler M, Heckel A, Godel T, Heiland S, Schlemmer HP, Jäger D, Bendszus M, Bäumer P. Dorsal root ganglia hypertrophy as in vivo correlate of oxaliplatin-induced polyneuropathy. PLoS One 2017; 12:e0183845. [PMID: 28837658 PMCID: PMC5570356 DOI: 10.1371/journal.pone.0183845] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Accepted: 08/12/2017] [Indexed: 02/07/2023] Open
Abstract
Purpose To investigate in vivo morphological and functional correlates of oxaliplatin-induced peripheral neuropathy (OXA-PNP) by magnetic resonance neurography (MRN). Methods Twenty patients (7 female, 13 male, 58.9±10.0 years) with mild to moderate OXA-PNP and 20 matched controls (8 female, 12 male, 55.7±15.6 years) were prospectively enrolled. All patients underwent a detailed neurophysiological examination prior to neuroimaging. A standardized imaging protocol at 3.0 Tesla included the lumbosacral plexus and both sciatic nerves and their branches using T2-weighted fat-saturated sequences and diffusion tensor imaging. Quantitative assessment included volumetry of the dorsal root ganglia (DRG), sciatic nerve normalized T2 (nT2) signal and caliber, and fractional anisotropy (FA), mean diffusivity (MD), axial (AD) and radial diffusivity (RD). Additional qualitative evaluation of sciatic, peroneal, and tibial nerves evaluated the presence, degree, and distribution of nerve lesions. Results DRG hypertrophy in OXA-PNP patients (207.3±47.7mm3 vs. 153.0±47.1mm3 in controls, p = 0.001) was found as significant morphological correlate of the sensory neuronopathy. In contrast, peripheral nerves only exhibited minor morphological alterations qualitatively. Quantitatively, sciatic nerve caliber (27.3±6.7mm2 vs. 27.4±7.4mm2, p = 0.80) and nT2 signal were not significantly changed in patients (1.32±0.22 vs. 1.22±0.26, p = 0.16). AD, RD, and MD showed a non-significant decrease in patients, while FA was unchanged. Conclusion OXA-PNP manifests with morphological and functional correlates that can be detected in vivo by MRN. We report hypertrophy of the DRG that stands in contrast to experimental and postmortem studies. DRG volume should be further investigated as a biomarker in other sensory peripheral neuropathies and ganglionopathies.
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Affiliation(s)
- Leonidas Apostolidis
- Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg, Germany
| | - Daniel Schwarz
- Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany
| | - Annie Xia
- Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany
| | - Markus Weiler
- Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany
| | - Andreas Heckel
- Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany
| | - Tim Godel
- Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany
| | - Sabine Heiland
- Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany
| | | | - Dirk Jäger
- Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg, Germany
| | - Martin Bendszus
- Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany
| | - Philipp Bäumer
- Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany
- Department of Radiology, German Cancer Research Center, Heidelberg, Germany
- * E-mail:
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32
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Totzeck M, Mincu RI, Rassaf T. Cardiovascular Adverse Events in Patients With Cancer Treated With Bevacizumab: A Meta-Analysis of More Than 20 000 Patients. J Am Heart Assoc 2017; 6:JAHA.117.006278. [PMID: 28862931 PMCID: PMC5586462 DOI: 10.1161/jaha.117.006278] [Citation(s) in RCA: 112] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Background The monoclonal antibody bevacizumab effectively inhibits angiogenesis in several types of cancers by blocking vascular endothelial growth factor. However, life‐threatening cardiovascular adverse effects could limit its use and may warrant specific follow‐up strategies. Methods and Results We systematically searched MEDLINE, Cochrane, EMBASE, and Web of Science for randomized controlled trials published until November 2016 that assessed patients with cancer treated with or without bevacizumab in addition to standard chemotherapy. A total of 20 050 patients with a broad range of cancer types from 22 studies were included in this analysis (10 394 in the bevacizumab group and 9656 in the control group). The risks of arterial and venous adverse events were higher in the bevacizumab groups (relative risk [RR], 1.37; 95% CI, 1.10–1.70 [P=0.004] and RR, 1.29; 95% CI, 1.12–1.47 [P<0.001], respectively), and more arterial adverse events occurred in patients taking high‐dose bevacizumab regimens. Bevacizumab treatment was associated with the highest risk of cardiac and cerebral ischemia in the high‐dose bevacizumab groups (RR, 4.4; 95% CI, 1.59–12.70 [P=0.004] and RR, 6.67; 95% CI, 2.17–20.66 [P=0.001], respectively). In addition, the risk of bleeding and arterial hypertension were higher in the bevacizumab groups (RR, 2.74; 95% CI, 2.38–3.15 [P<0.001] and RR, 4.73; 95% CI, 4.15–5.39 [P<0.00001], respectively), with higher values for patiens taking high‐dose regimens. Conclusions Treatment with bevacizumab increases the risk of arterial adverse events, particularly cardiac and cerebral ischemia, venous adverse events, bleeding, and arterial hypertension. This risk is additionally increased with high doses of bevacizumab. Further studies should determine the appropriate options for cardio‐oncology management. Clinical Trial Registration URL: https://www.crd.york.ac.uk. Unique identifier: PROSPERO(CRD42016054305).
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Affiliation(s)
- Matthias Totzeck
- Department of Cardiology and Vascular Medicine, Medical Faculty, West German Heart and Vascular Center, University Hospital Essen, Essen, Germany
| | - Raluca Ileana Mincu
- Department of Cardiology and Vascular Medicine, Medical Faculty, West German Heart and Vascular Center, University Hospital Essen, Essen, Germany
| | - Tienush Rassaf
- Department of Cardiology and Vascular Medicine, Medical Faculty, West German Heart and Vascular Center, University Hospital Essen, Essen, Germany
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Zhu X, Ko YJ, Berry S, Shah K, Lee E, Chan K. A Bayesian network meta-analysis on second-line systemic therapy in advanced gastric cancer. Gastric Cancer 2017; 20:646-654. [PMID: 27722826 DOI: 10.1007/s10120-016-0656-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Accepted: 10/02/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND It is unclear which regimen is the most efficacious among the available therapies for advanced gastric cancer in the second-line setting. We performed a network meta-analysis to determine their relative benefits. METHODS We conducted a systematic review of randomized controlled trials (RCTs) through the MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases and American Society of Clinical Oncology abstracts up to June 2014 to identify phase III RCTs on advanced gastric cancer in the second-line setting. Overall survival (OS) data were the primary outcome of interest. Hazard ratios (HRs) were extracted from the publications on the basis of reported values or were extracted from survival curves by established methods. A Bayesian network meta-analysis was performed with WinBUGS to compare all regimens simultaneously. RESULTS Eight RCTs (2439 patients) were identified and contained extractable data for quantitative analysis. Network meta-analysis showed that paclitaxel plus ramucirumab was superior to single-agent ramucirumab [OS HR 0.51, 95 % credible region (CR) 0.30-0.86], paclitaxel (OS HR 0.81, 95 % CR 0.68-0.96), docetaxel (OS HR 0.56, 95 % CR 0.33-0.94), and irinotecan (OS HR 0.71, 95 % CR 0.52-0.99). Paclitaxel plus ramucirumab also had an 89 % probability of being the best regimen among all these regimens. Single-agent ramucirumab, paclitaxel, docetaxel, and irinotecan were comparable to each other with respect to OS and were superior to best supportive care. CONCLUSIONS This is the first network meta-analysis to compare all second-line regimens reported in phase III gastric cancer trials. The results suggest the paclitaxel plus ramucirumab combination is the most effective therapy and should be the reference regimen for future comparative trials.
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Affiliation(s)
- Xiaofu Zhu
- Cross Cancer Institute, Edmonton , AB, T6G 1Z2, Canada
| | - Yoo-Joung Ko
- Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, ON, M4N 3M5, Canada
| | - Scott Berry
- Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, ON, M4N 3M5, Canada
| | - Keya Shah
- Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, ON, M4N 3M5, Canada
| | - Esther Lee
- Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, ON, M4N 3M5, Canada
| | - Kelvin Chan
- Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, ON, M4N 3M5, Canada. .,Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, M5T 3M7, Canada. .,Canadian Centre for Applied Research in Cancer Control (ARCC), Toronto, Canada.
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He W, Chan CML, Wong SCC, Au TCC, Ho WS, Chan AKC, Chan ASK, Ma BBY, Chan ATC. Jagged 2 silencing inhibits motility and invasiveness of colorectal cancer cell lines. Oncol Lett 2016; 12:5193-5198. [PMID: 28105228 DOI: 10.3892/ol.2016.5321] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2014] [Accepted: 06/27/2016] [Indexed: 12/22/2022] Open
Abstract
Although the Notch pathway has been reported to be activated in colorectal cancer (CRC), limited information is available regarding the expression and role of its ligand, Jagged 2 (JAG2), in CRC. Using immunohistochemistry, the present study demonstrated that JAG2 protein expression may be detected in up to 95% of CRC cases and is 3-fold upregulated in tumor cells compared to surrounding normal tissues. This finding suggests that JAG2 may have a role in the tumorigenicity of CRC. To further investigate the cellular functions of JAG2 expression in CRC, two different small interfering RNAs (siRNAs) were used to downregulate JAG2 expression in CRC cell lines (HCT116, DLD-1 and HT-29). The results indicated that JAG2 knockdown inhibits the motility and invasiveness of CRC cell lines without significantly affecting cell proliferation. These findings implicate JAG2 in promoting aggressiveness of CRC, and lay the foundation for its future development as a therapeutic target for the treatment of CRC.
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Affiliation(s)
- Wan He
- Department of Oncology, Shenzhen People's Hospital, Second Clinical Medical College of Jinan University, Shenzhen, Guangdong 518029, P.R. China
| | - Charles Ming Lok Chan
- State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer, Department of Clinical Oncology, Hong Kong Cancer Institute and Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, P.R. China
| | - Sze Chuen Cesar Wong
- Department of Health Technology and Informatics, Hong Kong Polytechnic University, Hong Kong SAR, P.R. China
| | - Thomas Chi Chuen Au
- State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer, Department of Clinical Oncology, Hong Kong Cancer Institute and Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, P.R. China
| | - Wing Shan Ho
- State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer, Department of Clinical Oncology, Hong Kong Cancer Institute and Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, P.R. China
| | | | - Andrew Sai Kit Chan
- State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer, Department of Clinical Oncology, Hong Kong Cancer Institute and Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, P.R. China
| | - Brigette Buig Yue Ma
- State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer, Department of Clinical Oncology, Hong Kong Cancer Institute and Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, P.R. China
| | - Anthony Tak Cheung Chan
- State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer, Department of Clinical Oncology, Hong Kong Cancer Institute and Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, P.R. China
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Robinson AM, Stojanovska V, Rahman AA, McQuade RM, Senior PV, Nurgali K. Effects of Oxaliplatin Treatment on the Enteric Glial Cells and Neurons in the Mouse Ileum. J Histochem Cytochem 2016; 64:530-45. [PMID: 27389702 PMCID: PMC5006136 DOI: 10.1369/0022155416656842] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Accepted: 06/06/2016] [Indexed: 12/17/2022] Open
Abstract
Oxaliplatin, currently used for treatment of colorectal and other cancers, causes severe gastrointestinal side effects, including nausea, vomiting, diarrhea, and constipation that are attributed to mucosal damage. However, delayed onset and long-term persistence of these side effects suggest that damage to the enteric nervous system (ENS) regulating physiological function of the gastrointestinal tract may also occur. The ENS comprises myenteric and submucosal neurons and enteric glial cells (EGCs). This study aimed to investigate the effects of oxaliplatin treatment on enteric neurons and EGCs within the mouse ileum. BALB/c mice received repeated intraperitoneal injections of oxaliplatin (3 mg/kg, 3 injections/week). Tissues were collected 3, 7, 14, and 21 days from the commencement of treatment. Decreases in glial fibrillary acidic protein-immunoreactive (IR) EGCs and protein gene product 9.5/β-Tubulin III-IR neurons as well as increase in s100β-IR EGCs after chronic oxaliplatin administration were observed in both the myenteric and submucosal plexi. Changes in EGCs were further observed in cross-sections of the ileum at day 14 and confirmed by Western blotting. Alterations in EGCs correlated with loss of myenteric and submucosal neurons in the ileum from oxaliplatin-treated mice. These changes to the ENS may contribute to the mechanisms underlying gastrointestinal side effects associated with oxaliplatin treatment.
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Affiliation(s)
| | | | | | | | | | - Kulmira Nurgali
- Kulmira Nurgali, Western Centre for Health Research & Education, Sunshine Hospital, 176 Furlong Road, St Albans, VIC 3021, Australia.
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Ter Veer E, Haj Mohammad N, van Valkenhoef G, Ngai LL, Mali RMA, Anderegg MC, van Oijen MGH, van Laarhoven HWM. The Efficacy and Safety of First-line Chemotherapy in Advanced Esophagogastric Cancer: A Network Meta-analysis. J Natl Cancer Inst 2016; 108:djw166. [PMID: 27576566 DOI: 10.1093/jnci/djw166] [Citation(s) in RCA: 84] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Accepted: 05/27/2016] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND A globally accepted standard first-line chemotherapy regimen in advanced esophagogastric cancer (AEGC) is not clearly established. We conducted a systematic review to investigate the efficacy and safety of first-line chemotherapy using Network meta-analysis (NMA). METHODS Medline, EMBASE, CENTRAL, and conferences were searched until June 2015 for randomized controlled trials that compared regimens containing: fluoropyrimidine (F), platinum (cisplatin [C] and oxaliplatin [Ox]), taxane (T), anthracycline (A), irinotecan (I), or methotrexate (M). Direct and indirect evidence for overall survival (OS) and progression-free-survival (PFS) were combined using random-effects NMA on the hazard ratio (HR) scale and calculated as combined hazard ratios and 95% credible intervals (CrIs). RESULTS The NMA incorporated 17 chemotherapy regimens with 37 direct comparisons between regimens for OS (50 studies, n = 10 249) and 29 direct comparisons for PFS (34 studies, n = 7795). Combining direct and indirect effects showed increased efficacy for fluoropyrimidine noncisplatin doublets (F-doublets) over cisplatin doublets (C-doublets): FI vs CF (combined HR = 0.85, 95% CrI = 0.71 to 0.99), FOx vs CF (combined HR = 0.83, 95% CrI = 0.71 to 0.98) in OS and FOx vs CF (combined HR = 0.82, 95% CrI = 0.66 to 0.99) in PFS. Anthracycline-containing triplets (A-triplets: ACF, AFOx, AFM) and TCF triplet showed no benefit over F-doublets in OS and PFS. The triplet FOxT showed increased PFS vs F-doublets FT (combined HR = 0.61, 95% CrI = 0.38 to 0.99), FI (combined HR = 0.62, 95% CrI = 0.38 to 0.99), and FOx (combined HR = 0.67, 95% CrI = 0.44 to 0.99). Increased grade 3 to 4 toxicity was found for CF vs F-doublets, for ACF vs FI for TCF vs CF, and for FOxT vs FOx. CONCLUSIONS Based on efficacy and toxicity, F-doublets FOx, FI, and FT are preferred as first-line treatment for AEGC compared with C-doublets, A-triplets, and TCF. FOxT is the most promising triplet.
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Affiliation(s)
- Emil Ter Veer
- Affiliations of author: Department of Medical Oncology (EtV, NHM, LLN, RM, MGHvO, HWMvL) and Department of Surgery (MCA), Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands; Department of Epidemiology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands (GvV)
| | - Nadia Haj Mohammad
- Affiliations of author: Department of Medical Oncology (EtV, NHM, LLN, RM, MGHvO, HWMvL) and Department of Surgery (MCA), Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands; Department of Epidemiology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands (GvV)
| | - Gert van Valkenhoef
- Affiliations of author: Department of Medical Oncology (EtV, NHM, LLN, RM, MGHvO, HWMvL) and Department of Surgery (MCA), Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands; Department of Epidemiology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands (GvV)
| | - Lok Lam Ngai
- Affiliations of author: Department of Medical Oncology (EtV, NHM, LLN, RM, MGHvO, HWMvL) and Department of Surgery (MCA), Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands; Department of Epidemiology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands (GvV)
| | - Rosa M A Mali
- Affiliations of author: Department of Medical Oncology (EtV, NHM, LLN, RM, MGHvO, HWMvL) and Department of Surgery (MCA), Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands; Department of Epidemiology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands (GvV)
| | - Maarten C Anderegg
- Affiliations of author: Department of Medical Oncology (EtV, NHM, LLN, RM, MGHvO, HWMvL) and Department of Surgery (MCA), Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands; Department of Epidemiology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands (GvV)
| | - Martijn G H van Oijen
- Affiliations of author: Department of Medical Oncology (EtV, NHM, LLN, RM, MGHvO, HWMvL) and Department of Surgery (MCA), Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands; Department of Epidemiology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands (GvV)
| | - Hanneke W M van Laarhoven
- Affiliations of author: Department of Medical Oncology (EtV, NHM, LLN, RM, MGHvO, HWMvL) and Department of Surgery (MCA), Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands; Department of Epidemiology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands (GvV)
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Lewis C, Xun P, He K. Effects of adjuvant chemotherapy on recurrence, survival, and quality of life in stage II colon cancer patients: a 24-month follow-up. Support Care Cancer 2015; 24:1463-71. [DOI: 10.1007/s00520-015-2931-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Accepted: 08/31/2015] [Indexed: 10/23/2022]
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Munding J, Tannapfel A. Epidemiology of Colorectal Adenomas and Histopathological Assessment of Endoscopic Specimens in the Colorectum. VISZERALMEDIZIN 2015; 30:10-6. [PMID: 26288577 PMCID: PMC4513795 DOI: 10.1159/000357744] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
BACKGROUND Colorectal cancer is one of the most frequently observed neoplasms in the world. It develops from intraepithelial neoplasia of the colorectal mucosa, and these precursor lesions are also known as adenoma. As the precursor lesion is known and can be detected easily, efficient screening strategies are available for a reliable prevention of colorectal adenocarcinoma, e.g. by colonoscopy. METHODS Literature databases (PubMed) were searched selectively for the keywords 'colorectal adenoma', 'epidemiology', and 'resection techniques'. The results are presented in the following text, also taking into account our own experience and the current S3 guidelines. RESULTS Endoscopic resection samples are one of the specimens most frequently assessed by pathologists. Therefore, gastroenterologists expect standardized and well-structured pathology reports, stating relevant information concerning the removed lesions and recommendations for clinical management. These aspects are summarized in the evidence-based S3 guideline. CONCLUSION As a consequence of colorectal adenoma resection during screening procedures, the carcinoma incidence is decreasing. For further advancements in successful prevention, knowledge of different precursor lesions (conventional adenoma, serrated adenoma) is important, but also structured communication between the different disciplines engaged in colorectal cancer screening.
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Osoegawa A, Kometani T, Fukuyama S, Hirai F, Seto T, Sugio K, Ichinose Y. Prognostic Factors for Survival after Resection of Pulmonary Metastases from Colorectal Carcinoma. Ann Thorac Cardiovasc Surg 2015; 22:6-11. [PMID: 26289631 DOI: 10.5761/atcs.oa.14-00345] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
PURPOSE As chemotherapy has improved, the survival of patients with metastatic colorectal carcinoma has reached up to 2.5 years. Many of these patients experience pulmonary metastases; however, the prognosis after pulmonary metastasectomy is not satisfying. In this study, we analyzed the prognostic factors for survival in patients who underwent pulmonary metastasectomy. METHODS Eighty-seven patients with colorectal carcinoma received pulmonary metastasectomy. The pathological status of the primary tumor, outcome of the pulmonary metastasectomy, disease-free interval, perioperative carcinoembryonic antigen (CEA) level and history of liver metastases were assessed. RESULTS The five-year survival was 42.5% after pulmonary metastasectomy. A univariate analyses revealed that the CEA level (p = 0.043) and the number of pulmonary metastases (p = 0.047) were prognostic factors for survival. The CEA level was an independent prognostic factor in a multivariate analysis (relative risk = 2.01, p = 0.037). Among cases with elevated preoperative CEA levels, those whose CEA level normalized after metastasectomy had a better prognosis compared with those whose CEA level decreased but was still high, or whose level increased after metastasectomy (median survival time of 41.8 months compared with 28.1 or 15.7 months, respectively p = 0.021). CONCLUSION The CEA level can be a predictive marker for the prognosis in patients with pulmonary metastases from colorectal carcinoma.
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Affiliation(s)
- Atsushi Osoegawa
- Department of Thoracic Oncology, National Kyushu Cancer Center, Fukuoka, Fukuoka, Japan
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Kawaguchi K, Uehara K, Nakayama G, Fukui T, Fukumoto K, Nakamura S, Yokoi K. Growth rate of chemotherapy-naïve lung metastasis from colorectal cancer could be a predictor of early relapse after lung resection. Int J Clin Oncol 2015; 21:329-334. [PMID: 26280748 DOI: 10.1007/s10147-015-0889-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Accepted: 08/04/2015] [Indexed: 12/24/2022]
Abstract
PURPOSE The aim of this study was to elucidate a potential risk factor for early relapse after pulmonary metastasectomy of colorectal cancer and to propose an optimal treatment strategy for lung metastasis with an aggressive nature. METHODS Seventy patients who underwent pulmonary metastasectomy for diachronically measurable pulmonary lesions were retrospectively analyzed. We calculated the tumor doubling time (TDT) as the growth rate of lung metastasis and divided the study population into two groups: Rapid (TDT ≤ 100 days) and Slow (TDT > 100 days). RESULTS The patients consisted of 47 males and 23 females, with a mean age of 63 years. Forty-two patients had a relapse after pulmonary metastasectomy with a median follow-up duration of 24 months. There was a significant difference in relapse-free survival between the Rapid and Slow groups (p = 0.047). Using a multivariate analysis, no preoperative chemotherapy and a high level of serum carcinoembryonic antigen were proven to be significant risk factors for relapse after metastasectomy. Meanwhile, multivariate analyses among 37 patients without preoperative chemotherapy indicated that TDT was the sole significant factor for relapse-free survival. In addition, eight of nine patients with relapse within 12 months were placed into the Rapid group. CONCLUSIONS Although this was a preliminary study with a small number of patients, it suggested that lung metastases demonstrating a TDT of 100 days or less have a high risk of early relapse after metastasectomy.
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Affiliation(s)
- Koji Kawaguchi
- Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Keisuke Uehara
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Goro Nakayama
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Takayuki Fukui
- Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Koichi Fukumoto
- Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Shota Nakamura
- Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Kohei Yokoi
- Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
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Abstract
The response to first-line therapy is a primary determinant of outcome in patients with metastatic colorectal cancer (mCRC), for three main reasons: effective upfront therapy provides a unique opportunity to cure some patients; can be crucial in delaying disease progression and achieving symptom relief; and can improve patient eligibility for, and the effectiveness of, further treatments. In the past decade, decision-making regarding the choice of first-line therapy for mCRC has been complicated by the availability of many different options without a definitive consensus on a specific standard of care (despite major advances in categorizing predictive molecular disease subtypes). Most of the efforts of the scientific community have been directed at establishing the best biologic agent to be combined with a chemotherapy doublet, although a different branch of research has produced new data that underscore the importance of defining the optimal chemotherapy backbone. Herein, we review the key clinical trials completed in the past 10 years that have investigated and compared the use of chemotherapy doublets, triplets, and monotherapies, with or without molecularly targeted biologic agents, in the first-line treatment of patients with mCRC. Our examination of the literature led us to propose a new patient-oriented algorithm to guide clinicians' decisions on the best choice of upfront therapy for mCRC.
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Yan M, Kumachev A, Siu LL, Chan KKW. Chemoradiotherapy regimens for locoregionally advanced nasopharyngeal carcinoma: A Bayesian network meta-analysis. Eur J Cancer 2015; 51:1570-9. [PMID: 26044925 DOI: 10.1016/j.ejca.2015.04.027] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Accepted: 04/30/2015] [Indexed: 10/23/2022]
Abstract
BACKGROUND Concurrent chemoradiotherapy followed by adjuvant chemotherapy (CRT-A) is often the regimen of choice in locoregionally advanced nasopharyngeal carcinoma (NPC). Many alternative regimens have been reported in the literature, however, it is unknown how effective these regimens are compared to each other due to the lack of direct comparisons. Our objective was to perform a network meta-analysis (NMA) to determine the relative survival benefits of these treatments for locoregionally advanced NPC. METHODS We performed a systematic review following the Cochrane methodology, using MEDLINE, EMBASE and CENTRAL to identify all randomised controlled trials (RCTs) that compared different chemoradiotherapy regimens for locoregionally advanced NPC. Overall survival (OS) was the primary outcome of interest, and hazard ratios (HRs) were extracted using the Parmar method. Bayesian NMAs with random effects were conducted using WinBUGS. RESULTS Twenty-five RCTs (5576 patients) were included in this review. All together, these trials compared seven different regimens: radiotherapy (RT), concurrent chemoradiotherapy (CRT), neoadjuvant followed by CRT (N-CRT), CRT-A, RT-A, N-RT and N-RT-A. All regimens that contained CRT performed significantly better than RT. CRT-A did not improve survival compared to CRT alone (0.98; 95% credible regions: 0.71-1.34). For N-CRT versus CRT, the HR was 1.03 (0.69-1.47). When CRT-A was compared against N-CRT, the resulting HR was 0.96 (0.64-1.48). CONCLUSIONS Adjuvant chemotherapy does not appear to improve survival following CRT. The efficacies of CRT, CRT-A and N-CRT all appeared to be similar. Further studies are warranted to determine the value of additional chemotherapy phases in specific patient subgroups.
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Affiliation(s)
- Marie Yan
- Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada
| | - Alexander Kumachev
- Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada
| | - Lillian L Siu
- Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada; Division of Medical Oncology, Princess Margaret Cancer Centre, 610 University Ave, Toronto, Ontario M5G 2M9, Canada
| | - Kelvin K W Chan
- Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada; Division of Medical Oncology, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada.
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Marschner N, Arnold D, Engel E, Hutzschenreuter U, Rauh J, Freier W, Hartmann H, Frank M, Jänicke M. Oxaliplatin-based first-line chemotherapy is associated with improved overall survival compared to first-line treatment with irinotecan-based chemotherapy in patients with metastatic colorectal cancer - Results from a prospective cohort study. Clin Epidemiol 2015; 7:295-303. [PMID: 25945067 PMCID: PMC4408959 DOI: 10.2147/clep.s73857] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
PURPOSE Several randomized trials investigating the preferable first-line combination chemotherapy regimen for metastatic colorectal cancer have shown inconsistent findings. Because a substantial number of patients are still being treated with "chemo-only" first-line therapies without targeted agents, we compared overall survival (OS) of patients treated in routine practice with oxaliplatin-fluoropyrimidine and irinotecan-fluoropyrimidine. PATIENTS AND METHODS Using the database of the Tumor Registry Colorectal Cancer, we identified 605 patients with metastatic colorectal cancer who received first-line fluoropyrimidine combination chemotherapy with either oxaliplatin (n=430) or irinotecan (n=175). The Tumor Registry Colorectal Cancer is a cohort study that prospectively documents treatment of colorectal cancer by office-based medical oncologists in Germany and has recruited over 5,000 patients. OS was estimated using the Kaplan-Meier method, and a multivariate Cox proportional hazard model was used to adjust for potentially confounding variables. RESULTS Median OS was 26.8 (95% confidence interval [CI] 22.4-31.9) months with an oxaliplatin-fluoropyrimidine combination and 18.3 (95% CI 15.1-23.2) months with irinotecan-fluoropyrimidine first-line "chemo-only" therapy. Median progression-free survival was 9.0 (8.1-10.2) and 7.9 (7.2-10.2) months, respectively. The difference in OS was confirmed if analysis was restricted to patients with synchronous metastases (no prior treatment). Among other variables, proportion of patients receiving any second-line therapy did not differ between groups. Oxaliplatin-based first-line therapy was associated with improved OS in multivariate analysis adjusted for potentially confounding variables (hazard ratio 0.678, 95% CI 0.510-0.901, P=0.007). CONCLUSION In clinical routine practice, first-line treatment with oxaliplatin-fluoropyrimidine combination chemotherapy compared to irinotecan-fluoropyrimidine combination is associated with improved survival in patients with metastatic colorectal cancer, independent of all examined potentially confounding factors.
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Affiliation(s)
- Norbert Marschner
- Praxis für Interdisziplinäre Onkologie und Hämatologie, Freiburg, Germany
| | | | - Erik Engel
- Hämatologisch – Onkologische Praxis Altona, Hamburg, Germany
| | | | - Jacqueline Rauh
- Fachinternistische Gemeinschaftspraxis und Therapiezentrum, Witten, Germany
| | | | - Holger Hartmann
- Clinical Epidemiology and Health Economics, iOMEDICO, Freiburg, Germany
| | | | - Martina Jänicke
- Clinical Epidemiology and Health Economics, iOMEDICO, Freiburg, Germany
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Cotte E, Villeneuve L, Passot G, Boschetti G, Bin-Dorel S, Francois Y, Glehen O. GRECCAR 8: impact on survival of the primary tumor resection in rectal cancer with unresectable synchronous metastasis: a randomized multicentre study. BMC Cancer 2015; 15:47. [PMID: 25849254 PMCID: PMC4327953 DOI: 10.1186/s12885-015-1060-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2014] [Accepted: 01/29/2015] [Indexed: 12/15/2022] Open
Abstract
Background A majority of patients with rectal cancer and metastasis are not eligible to curative treatment because of an extensive and unresectable metastatic disease. Primary tumor resection is still debated in this situation. Rectal surgery treats or prevents the symptoms and avoids the risk of acute complications related to the primary tumor. Several studies on colorectal cancers seem to show interesting results in terms of survival in favor to the resection of the primary tumor. To date, no randomized trial or even a prospective study has assessed the impact of primary tumor resection on overall survival in patients with colorectal cancer with unresectable metastasis. All published studies were retrospective and included colon and rectal cancers. Rectal cancer is associated with specific problems related to the rectal surgery. Surgery is more complex, and may be source of more morbidity and postoperative functional dysfunctions (stoma, digestive, sexual, urinary) than colic surgery. On the other hand, symptoms related to the progression of rectal tumor are often very disabling: pain, rectal syndrome. Methods/Design GRECCAR 8 is a multicentre randomized open-label controlled trial aimed to evaluate the impact on survival of the primary tumor resection in rectal cancer with unresectable synchronous metastasis. Patients must undergo upfront systemic chemotherapy for at least 4 courses before inclusion. Patients with progressive metastatic disease during upfront chemotherapy will be excluded from the study. Patients will be randomly assigned in a 1:1 ratio to Arm A: primary tumor resection followed by systemic chemotherapy versus Arm B: systemic chemotherapy alone. Primary endpoint will be overall survival measured from the date of randomization to the date of death or to the end of follow-up (2 years). Secondary endpoints will include progression-free survival, quality of life, toxicity of chemotherapy, response of the primary tumor and metastatic disease to chemotherapy, postoperative morbidity and mortality, rate of patient not eligible for postoperative chemotherapy (arm A), primary tumor related complications and rate of emergency surgery (arm B). The number of patients needed is 290. Trial registration ClinicalTrial.gov: NCT02314182
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Kodaz H, Erdogan B, Hacibekiroglu I, Turkmen E, Gurkan H, Albayrak D, Tastekin E, Uzunoglu S, Cicin I. Impact of bevacizumab on survival outcomes in primary tumor resected metastatic colorectal cancer. Med Oncol 2014; 32:441. [PMID: 25502088 DOI: 10.1007/s12032-014-0441-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2014] [Accepted: 12/05/2014] [Indexed: 12/16/2022]
Abstract
We have studied the efficacy of bevacizumab in colorectal cancer with unresectable metastasis patients who had undergone resection of primary tumor. The patients with unresectable metastasis during diagnosis who had undergone resection of primary tumor without chemotherapy and the patients without resection of primary tumor were included. Among patients who had met the inclusion criteria, 46 patients with resection of primary tumor and 47 without resection of primary tumor were included in the study. A total of 93 unresectable metastatic colorectal cancer patients were included in the study. Median PFS was 9 months (95 % CI 7.37-10.62) in patients with resected primary tumor and bevacizumab containing first-line chemotherapy combination. Median PFS was 10 months (95 % CI 8.06-11.93) in patients without bevacizumab (P = 0.66) Median OS was 25 months (95 % CI 17.92-32.07) in patients with resected primary tumor and bevacizumab containing first-line chemotherapy combination. Median OS was 16 months (95 % CI 9.71-22.28) in patients without bevacizumab (P = 0.36) Median OS was 16 months (95 % CI 13.06-8.939) in patients without resected primary tumor and bevacizumab containing first-line chemotherapy combination. Median OS was 9 months (95 % CI 1.48-16.51) in patients without bevacizumab (P = 0.012). Bevacizumab seems ineffective in mCRC patients with resected primary tumor. An increase in number of retrospective literature data and randomized, prospective studies is required about this subject.
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Affiliation(s)
- Hilmi Kodaz
- Department of Medical Oncology, Faculty of Medicine, Trakya University, Edirne, Turkey,
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46
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Prise en charge chirurgicale des métastases hépatiques des cancers colorectaux. ONCOLOGIE 2014. [DOI: 10.1007/s10269-014-2464-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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't Lam-Boer J, Mol L, Verhoef C, de Haan AFJ, Yilmaz M, Punt CJA, de Wilt JHW, Koopman M. The CAIRO4 study: the role of surgery of the primary tumour with few or absent symptoms in patients with synchronous unresectable metastases of colorectal cancer--a randomized phase III study of the Dutch Colorectal Cancer Group (DCCG). BMC Cancer 2014; 14:741. [PMID: 25277170 PMCID: PMC4196118 DOI: 10.1186/1471-2407-14-741] [Citation(s) in RCA: 70] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2013] [Accepted: 09/23/2014] [Indexed: 12/16/2022] Open
Abstract
Background There is no consensus regarding resection of the primary tumour with few or absent symptoms in patients with synchronous unresectable metastatic colorectal cancer (CRC). A potential benefit of resection of the primary tumour is to prevent complications of the primary tumour in later stages of the disease. We here propose a randomized trial in order to demonstrate that resection of the primary tumour improves overall survival. Methods/design The CAIRO4 study is a multicentre, randomized, phase III study of the Dutch Colorectal Cancer Group (DCCG). Patients with synchronous unresectable metastases of CRC and few or absent symptoms of the primary tumour are randomized 1:1 between systemic therapy only, and resection of the primary tumour followed by systemic therapy. Systemic therapy will consist of fluoropyrimidine-based chemotherapy in combination with bevacizumab. The primary objective of this study is to determine the clinical benefit in terms of overall survival of initial resection of the primary tumour. Secondary endpoints include progression free survival, surgical morbidity, quality of life and the number of patients requiring resection of the primary tumour in the control arm. Discussion The CAIRO4 study is a multicentre, randomized, phase III study that will assess the benefit of resection of the primary tumour in patients with synchronous metastatic CRC. Trial registration The CAIRO4 study is registered at clinicaltrials.gov (NCT01606098)
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Affiliation(s)
- Jorine 't Lam-Boer
- Department of Surgery, Radboud university medical center, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
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Taflin H, Wettergren Y, Odin E, Derwinger K. Folate levels measured by LC-MS/MS in patients with colorectal cancer treated with different leucovorin dosages. Cancer Chemother Pharmacol 2014; 74:1167-74. [PMID: 25238909 PMCID: PMC4236605 DOI: 10.1007/s00280-014-2591-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2014] [Accepted: 09/10/2014] [Indexed: 12/28/2022]
Abstract
Purpose Calcium folinate (leucovorin), which is converted in vivo into biologically active folate, enhances the potency of 5-fluorouracil (5-FU)-based chemotherapy in colorectal cancer. A common dosage of leucovorin in adjuvant and palliative settings is 60 mg/m2. The aim was to determine the levels of tetrahydrofolate (THF), 5,10-methylenetetrahydrofolate (methyleneTHF), and 5-methyltetrahydrofolate (methylTHF) in tumour and mucosa of colorectal cancer patients who received different dosages of leucovorin intravenously at time of surgery. Methods Eighty patients scheduled for colorectal resection with indication of colorectal cancer were randomised into four groups to receive leucovorin at 0, 60, 200, or 500 mg/m2, respectively. Blood samples were taken 10 and 30 min after leucovorin administration. Biopsy samples from tumour and mucosa were collected and snap-frozen at surgery. The levels of THF, methyleneTHF, and methylTHF in tumour and mucosa were assessed by liquid chromatography electrospray ionisation tandem mass spectrometry (LC–MS/MS) and the results were related to clinical diagnosis and therapeutic regimens. Results The folate levels in tissue revealed extensive inter-individual variability. The mean methyleneTHF value for the four treatment groups were 880, 1,769, 3,024 and 3,723 pmol/gww. Only half of the patients who received 60 mg/m2 leucovorin had higher levels of methyleneTHF in tumour than patients who received 0 mg/m2 leucovorin. Rectal cancer patients had significantly lower levels of methyleneTHF compared with colon cancer patients. Conclusions There was a large inter-patient variability of tissue folate levels in colorectal cancer patients after supplementation with leucovorin at standardised dosage. High leucovorin doses were needed to exceed baseline methyleneTHF values, especially in rectal cancer patients. The results indicate that the standardised leucovorin dose may be insufficient to attain the full antitumour effect of 5-FU. Further studies are needed to establish whether higher dosage yields a better treatment response.
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Affiliation(s)
- Helena Taflin
- Department of Surgery, Institute of Clinical Sciences, The Sahlgrenska Academy at University of Gothenburg, The Sahlgrenska University Hospital/Östra, 41685, Gōteborg, Sweden,
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Liu WQ, Megale V, Borriello L, Leforban B, Montès M, Goldwaser E, Gresh N, Piquemal JP, Hadj-Slimane R, Hermine O, Garbay C, Raynaud F, Lepelletier Y, Demange L. Synthesis and structure–activity relationship of non-peptidic antagonists of neuropilin-1 receptor. Bioorg Med Chem Lett 2014; 24:4254-9. [DOI: 10.1016/j.bmcl.2014.07.028] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2014] [Revised: 07/09/2014] [Accepted: 07/10/2014] [Indexed: 12/13/2022]
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SMAD4 and TS expression might predict the risk of recurrence after resection of colorectal liver metastases. Clin Transl Oncol 2014; 17:133-8. [PMID: 25060566 DOI: 10.1007/s12094-014-1202-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2014] [Accepted: 07/02/2014] [Indexed: 01/01/2023]
Abstract
PURPOSE Colorectal liver metastases (CLM) have significant molecular heterogeneity, which contributes to the risk of recurrence following surgery. Most of the traditional scores intended to predict recurrence is based on clinicopathological variables and it is unclear whether incorporating molecular biomarkers might improve our assessment of the risk of recurrence. Our aim was to determine if molecular biomarkers might be associated with the risk of recurrence after surgery of CLM. PATIENTS AND METHODS A total of 121 patients diagnosed with colorectal cancer (CRC) with resected liver metastases were included. The role of several clinicopathological variables to predict patient's outcome after resection of liver metastases was analyzed. Eighteen genes related to CRC pathogenesis were also included in the analyses. Univariate and multivariate stepwise Cox regression analyses were performed to identify factors associated with recurrence and the risk of death. RESULTS Eight prognostic factors for progression-free survival and nine factors for overall survival were identified in the univariate analyses. After adjusting for other risk factors, only the expression of two molecular factors was associated with the risk of recurrence: TS (HR 0.631, 95 % CI 0.422-0.944) and SMAD4 (HR 1.680, 95 % CI 1.047-2.695). None of the variables was significantly associated with the risk of death in the multivariate analyses. CONCLUSIONS The prognostic significance of most traditional clinicopathological variables might be insufficient to define patients at risk for recurrence after liver metastases resection. Molecular biomarkers might improve the identification of patients with higher risk of recurrence.
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