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Wang F, Dai G, Deng Y, Tang Y, Wang W, Niu Z, Bi F, Zhu L, Guo Z, Yan J, Hu B, Tao M, Yang S, Zhang S, Wen L, Xu R. Efficacy and safety of chemotherapy combined with bevacizumab in Chinese patients with metastatic colorectal cancer: A prospective, multicenter, observational, non-interventional phase IV trial. Chin J Cancer Res 2021; 33:490-499. [PMID: 34584374 PMCID: PMC8435824 DOI: 10.21147/j.issn.1000-9604.2021.04.06] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 08/09/2021] [Indexed: 02/05/2023] Open
Abstract
OBJECTIVE Bevacizumab has an important and evolving role in improving outcomes in patients with metastatic colorectal cancer (mCRC) worldwide and was approved in China in 2010. However, there are limited real-world data on the efficacy and safety of chemotherapy regimens combined with bevacizumab in Chinese patients with mCRC. This observational, phase IV trial study aimed to obtain more experience on the efficacy and safety of bevacizumab combined with chemotherapy in Chinese mCRC patients. METHODS Between September 2013 and November 2016, patients with histologically confirmed mCRC were enrolled in a prospective, multicenter, observational, non-interventional phase IV trial at 26 centers across China. Eligible patients received different chemotherapeutic regimens combined with bevacizumab. The efficacy and safety data in the intention-to-treat study population were analyzed. RESULTS A total of 611 patients were included in the efficacy analysis. The median overall survival and median progression-free survival was 18.00 and 10.05 months, respectively. The objective response rate was 21.00% and disease control rate was 89.40%. In subgroup analyses, the survival differences were observed according to metastatic status, duration of treatment and elevation in blood pressure. A total of 613 patients were evaluable for safety assessments. And 569 (92.82%) patients reported at least one adverse event (AE), and 151 (24.63%) experienced grade 3 or higher AEs. The incidence of bevacizumab-associated AEs of special interest was reported in 31 (5.06%) patients with hypertension (n=12), abscesses and fistulae (n=7), bleeding (n=6), proteinuria (n=3), gastrointestinal perforation (n=2) and venous thrombotic events (n=1). CONCLUSIONS This observational phase IV trial broadens our experience and knowledge of bevacizumab in the Chinese population and provides a good indication of its overall efficacy and safety. Bevacizumab in combination with chemotherapy offers clinical benefits to Chinese patients with mCRC and has an acceptable and manageable safety profile.
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Affiliation(s)
- Fenghua Wang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Guanghai Dai
- Department of Medical Oncology, Chinese PLA General Hospital, Beijing 100853, China
| | - Yanhong Deng
- Department of Medical Oncology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
| | - Yong Tang
- Department of Medical Oncology, Xinjiang Medical University Cancer Hospital, Urumqi 830000, China
| | - Wei Wang
- Department of Medical Oncology, Foshan First People’s Hospital, Foshan 528010, China
| | - Zuoxing Niu
- Department of Medical Oncology, Shandong Cancer Hospital, Jinan 250117, China
| | - Feng Bi
- Department of Medical Oncology, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Liangjun Zhu
- Department of Medical Oncology, Jiangsu Cancer Hospital, Nanjing 210009, China
| | - Zengqing Guo
- Department of Medical Oncology, Fujian Cancer Hospital, Fuzhou 350014, China
| | - Jin Yan
- Department of Surgical Oncology, Sichuan Cancer Hospital, Chengdu 610041, China
| | - Bing Hu
- Department of Medical Oncology, Anhui Provincial Hospital, Hefei 230001, China
| | - Min Tao
- Department of Medical Oncology, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Shujun Yang
- Department of Medical Oncology, Henan Cancer Hospital, Zhengzhou 450003, China
| | - Suzhan Zhang
- Department of Medical Oncology, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Lu Wen
- Department of Medical Oncology, Shanxi Provincial Cancer Hospital, Taiyuan 030009, China
| | - Ruihua Xu
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
- Ruihua Xu. Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine. No. 651 Dongfeng East Road, Guangzhou 510060, China.
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Beca JM, Dai WF, Pataky RE, Tran D, Dvorani E, Isaranuwatchai W, Peacock S, Alvi R, Cheung WY, Earle CC, Gavura S, Chan KKW. Real-world Safety of Bevacizumab with First-line Combination Chemotherapy in Patients with Metastatic Colorectal Cancer: Population-based Retrospective Cohort Studies in Three Canadian Provinces. Clin Oncol (R Coll Radiol) 2021; 34:e7-e17. [PMID: 34456106 DOI: 10.1016/j.clon.2021.08.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 07/16/2021] [Accepted: 08/12/2021] [Indexed: 11/03/2022]
Abstract
AIMS To examine the real-world safety of adding bevacizumab to first-line irinotecan-based chemotherapy for patients with metastatic colorectal cancer (mCRC). MATERIALS AND METHODS Patients diagnosed with CRC in three Canadian provinces (Ontario, Saskatchewan and British Columbia) who received publicly funded bevacizumab and/or irinotecan from 2000 to 2016 were identified from cancer registries. Propensity score 1:1 matching (PSM) and inverse probability of treatment weighting (IPTW) were performed to contemporaneous and historical controls, adjusting for baseline demographic and clinical characteristics. Safety end points evaluated during first-line treatment plus 30 days included mortality within 30 days and all-cause-, chemotherapy- and bevacizumab-related hospitalisations. Chemotherapy- and bevacizumab-related visits were defined as hospitalisations for specific conditions commonly associated with chemotherapy (e.g. infections) or bevacizumab (e.g. arteriovenous thromboembolism) using most responsible diagnosis codes. In PSM and IPTW-weighted cohorts, we assessed event frequencies using odds ratios from logistic regressions and event rate ratios using negative binomial regression models. The results from each province and comparison were pooled using random-effects meta-analysis. RESULTS We identified 16 250 mCRC patients who received first-line irinotecan-based treatment. In PSM cohorts, bevacizumab was associated with fewer deaths within 30 days of treatment compared with contemporaneous (pooled odds ratio = 0.62; 95% confidence interval 0.50-0.75) and historical controls (pooled odds ratio = 0.73; 95% confidence interval 0.58-0.93). Hospitalisations were more frequent among patients treated with bevacizumab compared with historical controls but similar to contemporaneous controls. As patients receiving bevacizumab were exposed to a longer average treatment duration, across their full treatment duration, patients receiving bevacizumab had significantly lower rates of hospitalisations (contemporaneous pooled rate ratio = 0.56; 95% confidence interval 0.47-0.67; historical pooled rate ratio = 0.73; 95% confidence interval 0.56-0.95). Similar trends were observed for chemotherapy- and bevacizumab-related hospitalisations and in IPTW-weighted cohorts. DISCUSSION We did not observe any increase in rates of hospitalisation or death within 30 days of treatment among mCRC patients treated with bevacizumab plus chemotherapy versus chemotherapy alone; these findings should be interpreted with caution due to the risk of residual confounding.
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Affiliation(s)
- J M Beca
- Ontario Health (Cancer Care Ontario), Toronto, Ontario, Canada; Canadian Centre for Applied Research in Cancer Control, Toronto, Ontario, Canada.
| | - W F Dai
- Ontario Health (Cancer Care Ontario), Toronto, Ontario, Canada
| | - R E Pataky
- Canadian Centre for Applied Research in Cancer Control, Toronto, Ontario, Canada; BC Cancer, Vancouver, British Columbia, Canada
| | - D Tran
- Saskatchewan Cancer Agency, Saskatoon, Saskatchewan, Canada
| | - E Dvorani
- Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada
| | - W Isaranuwatchai
- Canadian Centre for Applied Research in Cancer Control, Toronto, Ontario, Canada; St. Michael's Hospital, Toronto, Ontario, Canada; University of Toronto, Toronto, Ontario, Canada
| | - S Peacock
- Canadian Centre for Applied Research in Cancer Control, Toronto, Ontario, Canada; BC Cancer, Vancouver, British Columbia, Canada; Simon Fraser University, Burnaby, British Columbia, Canada
| | - R Alvi
- Saskatchewan Cancer Agency, Saskatoon, Saskatchewan, Canada
| | - W Y Cheung
- Cancer Control Alberta, Tom Baker Cancer Centre, Calgary, Alberta, Canada
| | - C C Earle
- Canadian Partnership Against Cancer, Toronto, Ontario, Canada; Ontario Institute for Cancer Research, Toronto, Ontario, Canada; Sunnybrook Odette Cancer Centre, Toronto, Ontario, Canada
| | - S Gavura
- Ontario Health (Cancer Care Ontario), Toronto, Ontario, Canada
| | - K K W Chan
- Ontario Health (Cancer Care Ontario), Toronto, Ontario, Canada; Canadian Centre for Applied Research in Cancer Control, Toronto, Ontario, Canada; Sunnybrook Odette Cancer Centre, Toronto, Ontario, Canada
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Monteiro AR, Conde RS, Basto R, Sclafani F, Deleporte A, Hendlisz A, Dal Lago L. Targeted agents in older patients with gastrointestinal cancers - An overview. J Geriatr Oncol 2021; 12:1240-1252. [PMID: 34226158 DOI: 10.1016/j.jgo.2021.06.013] [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: 04/07/2021] [Revised: 06/12/2021] [Accepted: 06/25/2021] [Indexed: 12/24/2022]
Abstract
Targeted agents have been increasingly used in different malignancies and are associated with improved survival outcomes, including gastrointestinal cancers. Their use in the treatment of older patients is appealing given their favorable toxicity profile. In the last years, this subgroup of patients has been attracting increased interest given their representativeness and specific clinical needs. Nonetheless, the lack of data on efficacy and safety of standard treatments in older patients hinders proper evidence-based decision-making, leaving most therapeutic recommendations to be extrapolated from registration trials with low representation of older and frail patients. However, even if most decisions regarding the use of targeted agents in older patients with gastrointestinal cancer remain guided by subanalyses of large trials, data from recent older adult-specific trials are beginning to emerge, particularly in colorectal cancer. This review aims to summarize the existing evidence on treatment of older patients with gastrointestinal carcinomas (colon and rectum, stomach, esophagus, liver, and pancreas) with targeted agents (cetuximab, panitumumab, bevacizumab, ramucirumab, aflibercept, regorafenib, encorafenib, trastuzumab, sorafenib, lenvatinib, cabozantinib, erlotinib, olaparib), and place the evidence in a geriatric oncology perspective.
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Affiliation(s)
- Ana Raquel Monteiro
- Instituto Português de Oncologia de Coimbra Francisco Gentil, Department of Medical Oncology, Av. Bissaya Barreto 98, 3000-075 Coimbra, Portugal.
| | - Rita Saúde Conde
- Instituto Português de Oncologia de Lisboa Francisco Gentil, Department of Medical Oncology, Rua Professor Lima Basto, 1099-023 Lisboa, Portugal.
| | - Raquel Basto
- Instituto Português de Oncologia de Coimbra Francisco Gentil, Department of Medical Oncology, Av. Bissaya Barreto 98, 3000-075 Coimbra, Portugal.
| | - Francesco Sclafani
- Institut Jules Bordet, Department of Medicine, Blvd de Waterloo 121, 1000 Brussels, Belgium.
| | - Amélie Deleporte
- Institut Jules Bordet, Department of Medicine, Blvd de Waterloo 121, 1000 Brussels, Belgium.
| | - Alain Hendlisz
- Institut Jules Bordet, Department of Medicine, Blvd de Waterloo 121, 1000 Brussels, Belgium.
| | - Lissandra Dal Lago
- Institut Jules Bordet, Department of Medicine, Blvd de Waterloo 121, 1000 Brussels, Belgium.
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Temraz S, Mukherji D, Nassar F, Moukalled N, Shamseddine A. Treatment sequencing of metastatic colorectal cancer based on primary tumor location. Semin Oncol 2021; 48:119-129. [PMID: 34120762 DOI: 10.1053/j.seminoncol.2021.05.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Revised: 04/15/2021] [Accepted: 05/13/2021] [Indexed: 01/09/2023]
Abstract
Colorectal cancer is a heterogeneous disease with various clinical, molecular, and embryological differences related to the origin of the tumor from the right or left colon. Recent studies have demonstrated that tumor sidedness has both a prognostic and predictive value in metastatic colorectal cancer . Patients whose primary tumor originates from the left side of the colon and whose tumor's genome encodes wild-type RAS and BRAF should be offered cetuximab or panitumumab in the first-line treatment of metastatic disease or in subsequent lines. For tumors originating from the right side of the colon, anti-angiogenic treatment, particularly bevacizumab, is an option for this poor prognostic group until better options become available. Specifically, an aggressive initial approach with FOLFOXIRI plus bevacizumab is a treatment option in right-sided tumors under investigation. This report reviews the available data for the treatment of metastatic colorectal cancer according to the location of the primary tumor and proposes the optimal treatment sequencing strategy incorporating the site of origin of the tumor and molecular information into the decision-making process.
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Affiliation(s)
- Sally Temraz
- Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon.
| | - Deborah Mukherji
- Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Farah Nassar
- Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Nour Moukalled
- Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Ali Shamseddine
- Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
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Benson AB, Venook AP, Al-Hawary MM, Arain MA, Chen YJ, Ciombor KK, Cohen S, Cooper HS, Deming D, Farkas L, Garrido-Laguna I, Grem JL, Gunn A, Hecht JR, Hoffe S, Hubbard J, Hunt S, Johung KL, Kirilcuk N, Krishnamurthi S, Messersmith WA, Meyerhardt J, Miller ED, Mulcahy MF, Nurkin S, Overman MJ, Parikh A, Patel H, Pedersen K, Saltz L, Schneider C, Shibata D, Skibber JM, Sofocleous CT, Stoffel EM, Stotsky-Himelfarb E, Willett CG, Gregory KM, Gurski LA. Colon Cancer, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2021; 19:329-359. [PMID: 33724754 DOI: 10.6004/jnccn.2021.0012] [Citation(s) in RCA: 887] [Impact Index Per Article: 221.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Colon Cancer focuses on systemic therapy options for the treatment of metastatic colorectal cancer (mCRC), because important updates have recently been made to this section. These updates include recommendations for first-line use of checkpoint inhibitors for mCRC, that is deficient mismatch repair/microsatellite instability-high, recommendations related to the use of biosimilars, and expanded recommendations for biomarker testing. The systemic therapy recommendations now include targeted therapy options for patients with mCRC that is HER2-amplified, or BRAF V600E mutation-positive. Treatment and management of nonmetastatic or resectable/ablatable metastatic disease are discussed in the complete version of the NCCN Guidelines for Colon Cancer available at NCCN.org. Additional topics covered in the complete version include risk assessment, staging, pathology, posttreatment surveillance, and survivorship.
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Affiliation(s)
- Al B Benson
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | - Alan P Venook
- UCSF Helen Diller Family Comprehensive Cancer Center
| | | | | | | | | | - Stacey Cohen
- Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance
| | | | | | - Linda Farkas
- UT Southwestern Simmons Comprehensive Cancer Center
| | | | | | | | | | | | | | - Steven Hunt
- Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine
| | | | | | - Smitha Krishnamurthi
- Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute
| | | | | | - Eric D Miller
- The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute
| | - Mary F Mulcahy
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | | | | | | | | | - Katrina Pedersen
- Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine
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A phase I/II study of S-1 and irinotecan (IRIS) combined with cetuximab in patients with RAS wild-type metastatic colorectal cancer (KSCC1401). Cancer Chemother Pharmacol 2020; 86:285-294. [PMID: 32734398 DOI: 10.1007/s00280-020-04108-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 06/24/2020] [Indexed: 12/15/2022]
Abstract
PURPOSE This study was designed to assess the tolerability, efficacy, and safety of tri-weekly irinotecan plus S-1 (IRIS) and weekly cetuximab in patients with metastatic colorectal cancer (mCRC). METHODS The main eligibility criteria were RAS wild-type mCRC with no prior chemotherapy. S-1 was given orally at a dose of 40 mg/m2 (40-60 mg) twice for 2 weeks, followed by a 1-week rest. Irinotecan was given on day 1 of each cycle at a dose of 150 mg/m2. Cetuximab was administered on days 1 (400 mg/m2), 8 (250 mg/m2), and 15 (250 mg/m2), and then once weekly (250 mg/m2) thereafter. A standard 3 + 3 phase I dose de-escalation design was used to determine the maximum tolerated dose and the recommended dose (RD) of irinotecan. The primary end point of the Phase II study was overall response rate (ORR). RESULTS Between December 2014 and September 2017, 4 and 54 patients were enrolled in phase I and phase II studies, respectively. No dose-limiting toxicity was observed in the phase I study, and the RD of irinotecan was 150 mg/m2. In the phase II study, the ORR was 56.9% (90% confidence interval 44.4%-68.7%). The safety profile revealed that the most common grade 3/4 adverse events were neutropenia (31.4%), appetite loss (27.5%), hypokalemia (11.8%), and diarrhea (11.8%). Grade 3/4 hand-foot skin syndrome occurred in nine patients (9.8%). CONCLUSION This study showed that the efficacy and safety of IRIS combined with cetuximab were comparable to those for other first-line treatments. This regimen is a good candidate for first-line treatment of RAS wild-type mCRC.
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Cortellini A, Cannita K, Parisi A, Lanfiuti Baldi P, Venditti O, D'Orazio C, Dal Mas A, Calvisi G, Giordano AV, Vicentini V, Vicentini R, Felicioni L, Marchetti A, Buttitta F, Russo A, Ficorella C. Weekly alternate intensive regimen FIrB/FOx in metastatic colorectal cancer patients: an update from clinical practice. Onco Targets Ther 2019; 12:2159-2170. [PMID: 30988620 PMCID: PMC6438145 DOI: 10.2147/ott.s194745] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Background Several trials evaluated the role of intensive regimens, made of triplet chemotherapies plus bevacizumab, as first-line treatment for patients with metastatic colorectal cancer (mCRC). We previously reported, in a Phase II prospective study, the efficacy and the tolerability of FIrB/FOx regimen, reporting interesting results in terms of received dose intensities (rDIs) and safety. Methods We reported a retrospective update of 85 patients treated with FIrB/FOx, an intensive regimen of 5-fluorouracil, bevacizumab, and weekly alternate irinotecan and oxaliplatin, to confirm its feasibility in “real life”. Subgroup analyses were performed, particularly among patients treated with standard and modified FIrB/FOx (based on age, performance status, and/or comorbidities). Results Overall, 3-month objective response rate (ORR) and 6-month ORR were 75.9% and 55.3%, respectively. Median progression-free survival (PFS) and median overall survival (OS) were 14.4 and 34.9 months, respectively. Among the patients treated with standard and modified regimens, 3-month ORR, PFS, and OS were 75.8% and 76% (P=1.0000), 14.4 and 14.4 months (P=0.8589), and 37.8 and 26.6 months (P=0.7746), respectively. Among the K/NRAS wild-type and K/NRAS mutant patients, 3-month ORR, PFS, and OS were 95.2% and 74.5% (P=0.0526), 15.3 and 14.4 months (P=0.8753), and 37.8 and 51.4 months (P=0.8527), respectively. The rDIs were ≥80% of full doses both in the standard and in the modified regimens subgroups. Cumulative G3/4 toxicities were neutropenia (14.1%), diarrhea (17.6%), asthenia (9.4%), vomiting (5.6%), and hypertension (16.5%). Conclusion This update shows that intensive regimens such as FIrB/FOx are also feasible options for first-line treatment of mCRC patients in the “real-life” setting.
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Affiliation(s)
- Alessio Cortellini
- Medical Oncology, St Salvatore Hospital, University of L'Aquila, L'Aquila, Italy, .,Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy,
| | - Katia Cannita
- Medical Oncology, St Salvatore Hospital, University of L'Aquila, L'Aquila, Italy,
| | - Alessandro Parisi
- Medical Oncology, St Salvatore Hospital, University of L'Aquila, L'Aquila, Italy, .,Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy,
| | - Paola Lanfiuti Baldi
- Medical Oncology, St Salvatore Hospital, University of L'Aquila, L'Aquila, Italy,
| | - Olga Venditti
- Medical Oncology, St Salvatore Hospital, University of L'Aquila, L'Aquila, Italy,
| | - Carla D'Orazio
- Medical Oncology, St Salvatore Hospital, University of L'Aquila, L'Aquila, Italy, .,Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy,
| | - Antonella Dal Mas
- Department of Pathology, St Salvatore Hospital L'Aquila, L'Aquila, Italy
| | - Giuseppe Calvisi
- Department of Pathology, St Salvatore Hospital L'Aquila, L'Aquila, Italy
| | - Aldo V Giordano
- Diagnostic and Interventional Radiology, St Salvatore Hospital, University of L'Aquila, L'Aquila, Italy
| | - Vincenzo Vicentini
- Department of Hepatobiliar-Pancreatic and Emergency Surgery, St Salvatore Hospital, L'Aquila, Italy
| | - Roberto Vicentini
- Department of Hepatobiliar-Pancreatic and Emergency Surgery, St Salvatore Hospital, L'Aquila, Italy
| | - Lara Felicioni
- Oncological and Cardiovascular Molecular Medicine Department, Center for Excellence on Ageing and Translational Medicine (CeSI-MeT), University of Chieti-Pescara, Chieti, Italy
| | - Antonio Marchetti
- Center of Predictive Molecular Medicine, Center for Excellence on Ageing and Translational Medicine (CeSI-MeT), University of Chieti-Pescara, Chieti, Italy
| | - Fiamma Buttitta
- Oncological and Cardiovascular Molecular Medicine Department, Center for Excellence on Ageing and Translational Medicine (CeSI-MeT), University of Chieti-Pescara, Chieti, Italy
| | - Antonio Russo
- Medical Oncology Unit, Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy
| | - Corrado Ficorella
- Medical Oncology, St Salvatore Hospital, University of L'Aquila, L'Aquila, Italy, .,Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy,
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Kim EJ, Woo HS, Cho JH, Sym SJ, Baek JH, Lee WS, Kwon KA, Kim KO, Chung JW, Park DK, Kim YJ. Early experience with Watson for oncology in Korean patients with colorectal cancer. PLoS One 2019; 14:e0213640. [PMID: 30908530 PMCID: PMC6433269 DOI: 10.1371/journal.pone.0213640] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Accepted: 02/26/2019] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Watson for oncology (WFO) is a cognitive computing system providing decision support. We evaluated the concordance rates between the treatment options determined by WFO and those determined by a multidisciplinary team (MDT). METHODS We reviewed the medical charts of patients diagnosed with colorectal cancer who visited the MDT at a single tertiary medical center from November 2016 to April 2017. WFO classified the treatment options for specific patients into three categories: 'Recommended', 'For consideration', and 'Not recommended'. Concordance rates between the WFO- and MDT-determined chemotherapy options, and the factors that potentially influence the concordance rate, were analyzed. RESULTS Sixty-nine patients with colorectal cancer met with the MDT from Nov. 2016 to Feb. 2017. The mean age of the patients was 62 years (range: 34-86 years), and more patients were male (47/69) than female. Of the 69 patients, 51 (73.9%) were diagnosed with colon cancer, of whom 46.4% received the same regimen recommendation from WFO ('Recommended') as they did from the MDT. After inclusion of the 'For consideration' category from WFO, the concordance rate increased to 87.0%. The concordance rate between MDT and NCCN guidelines was 97.1%, and that between the WFO and NCCN guidelines was 88.4%. The concordance rates between WFO and MDT were significantly lower in patients with stage II, IIIC, or IV disease (P<0.001), and the colorectal cancer stage was the only statistically significant factor discriminating between WFO and MDT. CONCLUSIONS The concordance rate between chemotherapy regimens for colorectal cancer determined by MDT versus WFO recommendations was 46.4%. After including the 'For consideration' category from WFO, the concordance rate increased to 88.4%. Further modification and improvement of the WFO prioritizing algorithm used to recommend treatment may increase the usefulness of WFO in the clinic.
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Affiliation(s)
- Eui Joo Kim
- Division of Gastroenterology, Department of Internal Medicine, Gachon University Gil Medcal Center, Gachon University College of Medicine, Incheon, Republic of Korea
| | - Hyun Sun Woo
- Division of Gastroenterology, Department of Internal Medicine, Gachon University Gil Medcal Center, Gachon University College of Medicine, Incheon, Republic of Korea
| | - Jae Hee Cho
- Division of Gastroenterology, Department of Internal Medicine, Gachon University Gil Medcal Center, Gachon University College of Medicine, Incheon, Republic of Korea
| | - Sun Jin Sym
- Division of Oncology, Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon, Republic of Korea
| | - Jeong-Heum Baek
- Department of Surgery, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon, Republic of Korea
| | - Won-Suk Lee
- Department of Surgery, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon, Republic of Korea
| | - Kwang An Kwon
- Division of Gastroenterology, Department of Internal Medicine, Gachon University Gil Medcal Center, Gachon University College of Medicine, Incheon, Republic of Korea
| | - Kyoung Oh Kim
- Division of Gastroenterology, Department of Internal Medicine, Gachon University Gil Medcal Center, Gachon University College of Medicine, Incheon, Republic of Korea
| | - Jun-Won Chung
- Division of Gastroenterology, Department of Internal Medicine, Gachon University Gil Medcal Center, Gachon University College of Medicine, Incheon, Republic of Korea
| | - Dong Kyun Park
- Division of Gastroenterology, Department of Internal Medicine, Gachon University Gil Medcal Center, Gachon University College of Medicine, Incheon, Republic of Korea
| | - Yoon Jae Kim
- Division of Gastroenterology, Department of Internal Medicine, Gachon University Gil Medcal Center, Gachon University College of Medicine, Incheon, Republic of Korea
- * E-mail:
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Phase I/II study evaluating the safety and clinical efficacy of temsirolimus and bevacizumab in patients with chemotherapy refractory metastatic castration-resistant prostate cancer. Invest New Drugs 2018; 37:331-337. [DOI: 10.1007/s10637-018-0687-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Accepted: 10/16/2018] [Indexed: 10/27/2022]
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"Vessels in the Storm": Searching for Prognostic and Predictive Angiogenic Factors in Colorectal Cancer. Int J Mol Sci 2018; 19:ijms19010299. [PMID: 29351242 PMCID: PMC5796244 DOI: 10.3390/ijms19010299] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Revised: 01/08/2018] [Accepted: 01/11/2018] [Indexed: 12/22/2022] Open
Abstract
High expectations are placed upon anti-angiogenic compounds for metastatic colorectal cancer (mCRC), the first malignancy for which such type of treatment has been approved. Indeed, clinical trials have confirmed that targeting the formation of new vessels can improve in many cases clinical outcomes of mCRC patients. However, current anti-angiogenic drugs are far from obtaining the desirable or expected curative results. Many are the factors probably involved in such disappointing results, but particular attention is currently focused on the validation of biomarkers able to improve the direction of treatment protocols. Because clinical studies have clearly demonstrated that serum or tissue concentration of some angiogenic factors is associated with the evolution of the disease of mCRC patients, they are currently explored as potential biomarkers of prognosis and of tumor response to therapy. However, the complex biology underlying CRC -induced angiogenesis is a hurdle in finding rapid solutions. The aim of this review was to explore molecular mechanisms that determine the formation of tumor-associated vessels during CRC progression, and to discuss the potential role of angiogenic factors as diagnostic, prognostic and predictive biomarkers in CRC.
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Martchenko K, Schmidtmann I, Thomaidis T, Thole V, Galle PR, Becker M, Möhler M, Wehler TC, Schimanski CC. Last line therapy with sorafenib in colorectal cancer: A retrospective analysis. World J Gastroenterol 2016; 22:5400-5405. [PMID: 27340356 PMCID: PMC4911348 DOI: 10.3748/wjg.v22.i23.5400] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Accepted: 01/30/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To analyze the efficacy of last line sorafenib treatment in colorectal cancer patients.
METHODS: All patients receiving chemotherapy for colorectal cancer in the outpatient clinic of the University of Mainz since 2006 were retrospectively analyzed for last line sorafenib exposure. Charts of identified patients were analyzed for clinic-pathological parameters, like data on gender, age, date of initial diagnosis, UICC stage, number and kind of the pre-therapies, therapy start and end of sorafenib, sorafenib mediated treatment cessation, side effects, response rates, time to progression and overall survival.
RESULTS: Ten patients with a median of 3.0 prior chemotherapy lines had received a last line sorafenib therapy either alone (10%) or in combination with 5-fluorouracil derivates (90%). All patients suffered from colorectal cancer stage UICC 4 and were routinely seen in 2-wk intervals in the oncology outpatient clinic. Median duration of treatment was 142.0 d. At 8 wk 80% of patients showed stable disease but we did not observe any remissions. Median time to progression was 140.5 d (4.7 mo), while median overall survival reached 176.5 d. One patient ceased treatment due to side effects. Reason for treatment stop was bleeding complication in one case and non-specified sorafenib intolerance in another case. Due to the retrospective approach we did not further quantify side effects.
CONCLUSION: This retrospective analysis encourages further investigation of sorafenib in colorectal cancer last line therapy.
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12
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Yamazaki K, Nagase M, Tamagawa H, Ueda S, Tamura T, Murata K, Eguchi Nakajima T, Baba E, Tsuda M, Moriwaki T, Esaki T, Tsuji Y, Muro K, Taira K, Denda T, Funai S, Shinozaki K, Yamashita H, Sugimoto N, Okuno T, Nishina T, Umeki M, Kurimoto T, Takayama T, Tsuji A, Yoshida M, Hosokawa A, Shibata Y, Suyama K, Okabe M, Suzuki K, Seki N, Kawakami K, Sato M, Fujikawa K, Hirashima T, Shimura T, Taku K, Otsuji T, Tamura F, Shinozaki E, Nakashima K, Hara H, Tsushima T, Ando M, Morita S, Boku N, Hyodo I. Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G). Ann Oncol 2016; 27:1539-46. [PMID: 27177863 DOI: 10.1093/annonc/mdw206] [Citation(s) in RCA: 176] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Accepted: 05/09/2016] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND FOLFIRI and FOLFOX have shown equivalent efficacy for metastatic colorectal cancer (mCRC), but their comparative effectiveness is unknown when combined with bevacizumab. PATIENTS AND METHODS WJOG4407G was a randomized, open-label, phase III trial conducted in Japan. Patients with previously untreated mCRC were randomized 1:1 to receive either FOLFIRI plus bevacizumab (FOLFIRI + Bev) or mFOLFOX6 plus bevacizumab (mFOLFOX6 + Bev), stratified by institution, adjuvant chemotherapy, and liver-limited disease. The primary end point was non-inferiority of FOLFIRI + Bev to mFOLFOX6 + Bev in progression-free survival (PFS), with an expected hazard ratio (HR) of 0.9 and non-inferiority margin of 1.25 (power 0.85, one-sided α-error 0.025). The secondary end points were response rate (RR), overall survival (OS), safety, and quality of life (QoL) during 18 months. This trial is registered to the University Hospital Medical Information Network, number UMIN000001396. RESULTS Among 402 patients enrolled from September 2008 to January 2012, 395 patients were eligible for efficacy analysis. The median PFS for FOLFIRI + Bev (n = 197) and mFOLFOX6 + Bev (n = 198) were 12.1 and 10.7 months, respectively [HR, 0.905; 95% confidence interval (CI) 0.723-1.133; P = 0.003 for non-inferiority]. The median OS for FOLFIRI + Bev and mFOLFOX6 + Bev were 31.4 and 30.1 months, respectively (HR, 0.990; 95% CI 0.785-1.249). The best overall RRs were 64% for FOLFIRI + Bev and 62% for mFOLFOX6 + Bev. The common grade 3 or higher adverse events were leukopenia (11% in FOLFIRI + Bev/5% in mFOLFOX6 + Bev), neutropenia (46%/35%), diarrhea (9%/5%), febrile neutropenia (5%/2%), peripheral neuropathy (0%/22%), and venous thromboembolism (6%/2%). The QoL assessed by FACT-C (TOI-PFC) and FACT/GOG-Ntx was favorable for FOLFIRI + Bev during 18 months. CONCLUSION FOLFIRI plus bevacizumab was non-inferior for PFS, compared with mFOLFOX6 plus bevacizumab, as the first-line systemic treatment for mCRC. CLINICAL TRIALS NUMBER UMIN000001396.
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Affiliation(s)
- K Yamazaki
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka
| | - M Nagase
- Department of Clinical Oncology, Jichi Medical University, Shimotsuke
| | - H Tamagawa
- Department of Surgery, Osaka General Medical Center, Osaka
| | - S Ueda
- Department of Medical Oncology, Kinki University Faculty of Medicine, Higashiosaka
| | - T Tamura
- Department of Medical Oncology, Nara Hospital Kinki University Faculty of Medicine, Ikoma
| | - K Murata
- Department of Surgery, Suita Municipal Hospital, Suita
| | - T Eguchi Nakajima
- Department of Clinical Oncology, St Marianna University School of Medicine, Kawasaki
| | - E Baba
- Department of Comprehensive Clinical Oncology, Kyushu University Faculty of Medical Sciences, Fukuoka
| | - M Tsuda
- Department of Gastroenterological Oncology, Hyogo Cancer Center, Akashi
| | - T Moriwaki
- Division of Gastroenterology, University of Tsukuba, Tsukuba
| | - T Esaki
- Department of Gastrointestinal and Medical Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka
| | - Y Tsuji
- Department of Medical Oncology, Tonan Hospital, Sapporo
| | - K Muro
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya
| | - K Taira
- Clinical Oncology, Osaka City General Hospital, Osaka
| | - T Denda
- Division of Gastroenterology, Chiba Cancer Center, Chiba
| | - S Funai
- Department of Surgery, Sakai Hospital Kinki University Faculty of Medicine, Sakai
| | - K Shinozaki
- Division of Clinical Oncology, Hiroshima Prefectural Hospital, Hiroshima
| | - H Yamashita
- Department of Gastroenterology and Hepatology, Okayama Medical Center, Okayama
| | - N Sugimoto
- Department of Clinical Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka
| | - T Okuno
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe
| | - T Nishina
- Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matuyama
| | - M Umeki
- Department of Surgery, Hyogo Prefectural Awaji Medical Center, Sumoto
| | - T Kurimoto
- Department of Gastrointestinal Oncology, Nagoya Kyoritsu Hospital, Nagoya
| | - T Takayama
- Department of Gastroenterology and Oncology, Tokushima University Graduate School, Tokushima
| | - A Tsuji
- Department of Medical Oncology, Kochi Health Sciences Center, Kochi
| | - M Yoshida
- Division of Cancer Chemotherapy Center, Osaka Medical College Hospital, Takatsuki
| | - A Hosokawa
- Department of Gastroenterology and Hematology, Faculty of Medicine, University of Toyama, Toyama
| | - Y Shibata
- Department of Chemotherapy, Miyazaki Prefectural Miyazaki Hospital, Miyazaki
| | - K Suyama
- Department of Medical Oncology, Toranomon Hospital, Tokyo
| | - M Okabe
- Department of Surgery, Kurashiki Central Hospital, Kurashiki
| | - K Suzuki
- Department of gastroenterology, Kushiro City General Hospital, Kushiro
| | - N Seki
- Division of Medical Oncology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo
| | - K Kawakami
- Department of Gastroenterology, Muroran City General Hospital, Muroran
| | - M Sato
- Department of Gastroenterology and Hepatology, Ryuugasaki Saiseikai Hospital, Ryugasaki
| | - K Fujikawa
- Department of Gastroenterology, Hokkaido Cancer Center, Sapporo
| | - T Hirashima
- Department of Thoracic Malignancy, Osaka Prefectural Medical Center for Respiratory and Allergic Diseases, Habikino
| | - T Shimura
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya
| | - K Taku
- Division of Medical Oncology, Shizuoka General Hospital, Shizuoka
| | - T Otsuji
- Department of Gastroenterology, Dongo Hospital, Yamatotakada
| | - F Tamura
- Department of Gastroenterology, Kumamoto Regional Medical Center, Kumamoto
| | - E Shinozaki
- Department of Gastroenterology, Cancer Institute Hospital of JFCR, Tokyo
| | - K Nakashima
- First Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki
| | - H Hara
- Department of Gastroenterology, Saitama Cancer Center, Saitama
| | - T Tsushima
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka
| | - M Ando
- Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya
| | - S Morita
- Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - N Boku
- Department of Clinical Oncology, St Marianna University School of Medicine, Kawasaki
| | - I Hyodo
- Division of Gastroenterology, University of Tsukuba, Tsukuba
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Aapro M, Scotte F, Bouillet T, Currow D, Vigano A. A Practical Approach to Fatigue Management in Colorectal Cancer. Clin Colorectal Cancer 2016; 16:275-285. [PMID: 29066018 DOI: 10.1016/j.clcc.2016.04.010] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2015] [Revised: 04/08/2016] [Accepted: 04/27/2016] [Indexed: 01/06/2023]
Abstract
Cancer-related fatigue is serious and complex, as well as one of the most common symptoms experienced by patients with colorectal cancer, with the potential to compromise quality of life, activities of daily living, and ultimately survival. There is a lack of consensus about the definition of cancer-related fatigue; however, definitions have been put forward by the European Association for Palliative Care (EAPC) and the National Comprehensive Cancer Network (NCCN). Numerous cancer- and treatment-related factors can contribute to fatigue, including disease progression, comorbidities, medical complications such as anemia, side effects of other medications, and a number of physical and psychologic factors. This underlines the importance of tackling factors that may contribute to fatigue before reducing the dose of treatment. NCCN guidelines and the EAPC have proposed approaches to managing fatigue in cancer patients; however, relatively few therapeutic agents have been demonstrated to reduce fatigue in randomized controlled trials. It is recognized that physical activity produces many beneficial physiologic modifications to markers of physical performance that can help to counteract various causes of fatigue. In appropriately managed and monitored patients with colorectal cancer, emerging evidence indicates that exercise programs may have a favorable influence on cancer-related fatigue, quality of life, and clinical outcomes, and therefore may help patients tolerate chemotherapy. This review assesses fatigue in patients with colorectal cancer and proposes updates to a treatment algorithm that may help clinicians manage this common problem.
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Affiliation(s)
- Matti Aapro
- Multidisciplinary Oncology Institute, Clinique de Genolier, Genolier, Switzerland.
| | - Florian Scotte
- Oncology Department, Georges Pompidou European Hospital, Paris, France
| | - Thierry Bouillet
- Oncology Department, University Hospital Avicenne, Bobigny, France
| | - David Currow
- Palliative and Supportive Services, Flinders University, Adelaide, Australia
| | - Antonio Vigano
- McGill Nutrition and Performance Laboratory and Division of Supportive and Palliative Care, McGill University Health Centre, Montreal, Canada
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14
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Siegelmann-Danieli N, Farkash A, Katzir I, Vesterman Landes J, Rotem Rabinovich H, Lomnicky Y, Carmeli B, Parush-Shear-Yashuv N. A Novel Computational Tool for Mining Real-Life Data: Application in the Metastatic Colorectal Cancer Care Setting. PLoS One 2016; 11:e0154689. [PMID: 27144545 PMCID: PMC4856262 DOI: 10.1371/journal.pone.0154689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2015] [Accepted: 04/18/2016] [Indexed: 12/05/2022] Open
Abstract
Background Randomized clinical trials constitute the gold-standard for evaluating new anti-cancer therapies; however, real-life data are key in complementing clinically useful information. We developed a computational tool for real-life data analysis and applied it to the metastatic colorectal cancer (mCRC) setting. This tool addressed the impact of oncology/non-oncology parameters on treatment patterns and clinical outcomes. Methods The developed tool enables extraction of any computerized information including comorbidities and use of drugs (oncological/non-oncological) per individual HMO member. The study in which we evaluated this tool was a retrospective cohort study that included Maccabi Healthcare Services members with mCRC receiving bevacizumab with fluoropyrimidines (FP), FP plus oxaliplatin (FP-O), or FP plus irinotecan (FP-I) in the first-line between 9/2006 and 12/2013. Results The analysis included 753 patients of whom 15.4% underwent subsequent metastasectomy (the Surgery group). For the entire cohort, median overall survival (OS) was 20.5 months; in the Surgery group, median duration of bevacizumab-containing therapy (DOT) pre-surgery was 6.1 months; median OS was not reached. In the Non-surgery group, median OS and DOT were 18.7 and 11.4 months, respectively; no significant OS differences were noted between FP-O and FP-I, whereas FP use was associated with shorter OS (12.3 month; p <0.002; notably, these patients were older). Patients who received both FP-O- and FP-I-based regimens achieved numerically longer OS vs. those who received only one of these regimens (22.1 [19.9–24.0] vs. 18.9 [15.5–21.9] months). Among patients assessed for wild-type KRAS and treated with subsequent anti-EGFR agent, OS was 25.4 months and 18.7 months for 124 treated vs. 37 non-treated patients (non-significant). Cox analysis (controlling for age and gender) identified several non-oncology parameters associated with poorer clinical outcomes including concurrent use of diuretics and proton-pump inhibitors. Conclusions Our tool provided insights that confirmed/complemented information gained from randomized-clinical trials. Prospective tool implementation is warranted.
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Affiliation(s)
| | - Ariel Farkash
- Department of Biomedical Informatics, IBM Research-Haifa, Haifa University Campus, Haifa, Israel
| | - Itzhak Katzir
- Department of Pharmacology, Maccabi Healthcare Services, Tel Aviv, Israel
| | | | | | - Yossef Lomnicky
- Department of Pharmacology, Maccabi Healthcare Services, Tel Aviv, Israel
| | - Boaz Carmeli
- Department of Biomedical Informatics, IBM Research-Haifa, Haifa University Campus, Haifa, Israel
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15
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Zhao H, Wang Y, Yu J, Wei F, Cao S, Zhang X, Dong N, Li H, Ren X. Autologous Cytokine-Induced Killer Cells Improves Overall Survival of Metastatic Colorectal Cancer Patients: Results From a Phase II Clinical Trial. Clin Colorectal Cancer 2016; 15:228-35. [PMID: 27052743 DOI: 10.1016/j.clcc.2016.02.005] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2015] [Revised: 12/31/2015] [Accepted: 02/03/2016] [Indexed: 01/20/2023]
Abstract
BACKGROUND This randomized clinical study was conducted to evaluate the therapeutic benefits of cytokine-induced killer (CIK) cell immunotherapy in combination with chemotherapy in metastatic colorectal cancer (mCRC) patients. PATIENTS AND METHODS Sixty-one patients in group 1 (cell therapy group) received autologous CIK cell immunotherapy in combination with chemotherapy (5-Fluorouridine, leucovorin and oxaliplatin [FOLFOX4] plan). Another 61 patients in group 2 (the control group) received chemotherapy (FOLFOX4 plan) alone. The primary study end points were overall survival (OS) and progression-free survival (PFS). The secondary end points were treatment response and adverse events. RESULTS The 3-year PFS and OS in group 1 were 20% and 48%, respectively, compared with 13% and 23%, respectively, in group 2 (P = .131 and P < .001, respectively). The median OS in group 1 was significantly increased compared with that in group 2 (OS, 36 vs. 16 months; P < .001). Furthermore, there was a trend toward superior PFS in group 1 compared with that in group 2 (PFS, 16 vs. 10 months; P = .072). Using univariate analysis, we found that Karnofsky performance status <80, number of metastases >1, and increased platelet levels were significantly associated with poorer prognosis in group 1. Alternatively, the cycle count of CIK cell treatment was significantly associated with good prognosis in group 1. Toxicity was mild in patients who received CIK therapy. CONCLUSION This study shows that CIK cell immunotherapy in combination with chemotherapy is well tolerated and improves the OS of mCRC patients.
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Affiliation(s)
- Hua Zhao
- National Clinical Research Center for Cancer, Key Laboratory Cancer and Therapy, Tianjin, PR China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, PR China
| | - Yang Wang
- National Clinical Research Center for Cancer, Key Laboratory Cancer and Therapy, Tianjin, PR China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, PR China
| | - Jinpu Yu
- National Clinical Research Center for Cancer, Key Laboratory Cancer and Therapy, Tianjin, PR China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, PR China
| | - Feng Wei
- National Clinical Research Center for Cancer, Key Laboratory Cancer and Therapy, Tianjin, PR China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, PR China
| | - Shui Cao
- National Clinical Research Center for Cancer, Key Laboratory Cancer and Therapy, Tianjin, PR China; Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, PR China
| | - Xinwei Zhang
- National Clinical Research Center for Cancer, Key Laboratory Cancer and Therapy, Tianjin, PR China; Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, PR China
| | - Nan Dong
- National Clinical Research Center for Cancer, Key Laboratory Cancer and Therapy, Tianjin, PR China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, PR China
| | - Hui Li
- National Clinical Research Center for Cancer, Key Laboratory Cancer and Therapy, Tianjin, PR China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, PR China.
| | - Xiubao Ren
- National Clinical Research Center for Cancer, Key Laboratory Cancer and Therapy, Tianjin, PR China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, PR China; Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, PR China.
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16
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Cremolini C, Loupakis F, Masi G, Lonardi S, Granetto C, Mancini ML, Chiara S, Moretto R, Rossini D, Vitello S, Allegrini G, Tonini G, Bergamo F, Tomasello G, Ronzoni M, Buonadonna A, Bustreo S, Barbara C, Boni L, Falcone A. FOLFOXIRI or FOLFOXIRI plus bevacizumab as first-line treatment of metastatic colorectal cancer: a propensity score-adjusted analysis from two randomized clinical trials. Ann Oncol 2016; 27:843-9. [PMID: 26861604 DOI: 10.1093/annonc/mdw052] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Accepted: 02/03/2016] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND FOLFOXIRI plus bevacizumab is a valid option as upfront treatment for metastatic colorectal cancer (mCRC) patients. While several trials investigated the effect of combining bevacizumab with different chemotherapy regimens, including fluoropyrimidines monotherapy and oxaliplatin- or irinotecan-containing doublets, no randomized comparison assessing the impact of the addition of bevacizumab to FOLFOXIRI is available. PATIENTS AND METHODS A total of 122 mCRC patients received first-line FOLFOXIRI in the phase III trial by the GONO (FOLFOXIRI group) and 252 patients received first-line FOLFOXIRI plus bevacizumab in the TRIBE trial (FOLFOXIRI plus bevacizumab group). A propensity score-adjusted method was adopted to provide an estimation of the benefit from the addition of bevacizumab to FOLFOXIRI in terms of survival and activity parameters. RESULTS Patients in the FOLFOXIRI group had more frequently Eastern Cooperative Oncology Group performance status of one or two, high Köhne score, metachronous and liver-limited disease, had previously received adjuvant treatments and had their primary tumors resected. The median progression-free survival (PFS) was 12.3 months in the FOLFOXIRI plus bevacizumab group compared with 10.0 months in the FOLFOXIRI group {propensity score-adjusted hazard ratio (HR) 0.74 [95% confidence interval (CI) 0.59-0.94], P = 0.013}. This association was significant also in the multivariable model (P = 0.024). The median OS was 29.8 months in the FOLFOXIRI plus bevacizumab group compared with 23.6 months in the FOLFOXIRI group [propensity score-adjusted HR: 0.72 (95% CI 0.56-0.93), P = 0.014]. At the multivariable model, the addition of bevacizumab was still associated with significantly longer OS (P = 0.030). No significant differences in RECIST response rate (RR) [65.1% versus 55.7%; propensity score-adjusted odds ratio (OR): 1.29 (95% CI 0.81-2.05), P = 0.280], early RR [62.7% versus 57.8%; OR: 1.14 (95% CI 0.68-1.93), P = 0.619] and median depth of response (42.2% versus 53.8%, P = 0.259) were reported. CONCLUSIONS Though in the absence of a randomized comparison, the addition of bevacizumab to FOLFOXIRI provides significant benefit in PFS and OS, thus supporting the use of FOLFOXIRI plus bevacizumab as upfront treatment for mCRC patients. TRIALS' NUMBERS NCT01219920 and NCT00719797.
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Affiliation(s)
- C Cremolini
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa
| | - F Loupakis
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa
| | - G Masi
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa
| | - S Lonardi
- Unit of Medical Oncology 1, Istituto Oncologico Veneto, IRCSS, Padua
| | - C Granetto
- Unit of Medical Oncology, Azienda Sanitaria Ospedaliera Santa Croce e Carle, Cuneo
| | - M L Mancini
- Department of Medical Oncology, University of Rome La Sapienza, Rome
| | - S Chiara
- Department of Medical Oncology 2, IRCCS Azienda Ospedaliera Universitaria San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genoa
| | - R Moretto
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa
| | - D Rossini
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa
| | - S Vitello
- Unit of Oncology, Sant'Elia Hospital, Caltanissetta
| | - G Allegrini
- Unit of Medical Oncology, 'Felice Lotti' Hospital, Pontedera
| | - G Tonini
- Department of Medical Oncology, University Campus Biomedico, Rome
| | - F Bergamo
- Unit of Medical Oncology 1, Istituto Oncologico Veneto, IRCSS, Padua
| | - G Tomasello
- Division of Medicine and Medical Oncology, Azienda Istituti Ospitalieri, Cremona
| | - M Ronzoni
- Department of Oncology, 'San Raffaele' Hospital IRCSS, Milan
| | - A Buonadonna
- Division of Oncology, Centro di Riferimento Oncologico, Aviano
| | - S Bustreo
- ColoRectal Cancer Unit, Unit of Oncology 1, 'Molinette' Hospital, Città della Salute e della Scienza, Turin
| | - C Barbara
- Unit of Medical Oncology, Spedali Riuniti di Livorno, Livorno
| | - L Boni
- Clinical Trials Coordinating Center, Istituto Toscano Tumori, Florence, Italy
| | - A Falcone
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa
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17
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Bordonaro R, Cordio S, Uccello M, Martines C, Fassari GE. Bevacizumab Plus Chemotherapy Cost Effectiveness. J Clin Oncol 2015; 33:3840-1. [DOI: 10.1200/jco.2015.62.0195] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Affiliation(s)
- Roberto Bordonaro
- Azienda Ospedaliera di Rilievo Nazionale e Alta Specializzazione (ARNAS) Garibaldi, Catania, Italy
| | - Stefano Cordio
- Azienda Ospedaliera di Rilievo Nazionale e Alta Specializzazione (ARNAS) Garibaldi, Catania, Italy
| | - Mario Uccello
- Azienda Ospedaliera di Rilievo Nazionale e Alta Specializzazione (ARNAS) Garibaldi, Catania, Italy
| | - Concetta Martines
- Azienda Ospedaliera di Rilievo Nazionale e Alta Specializzazione (ARNAS) Garibaldi, Catania, Italy
| | - Giuseppina E. Fassari
- Azienda Ospedaliera di Rilievo Nazionale e Alta Specializzazione (ARNAS) Garibaldi, Catania, Italy
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18
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Negri FV, Crafa P, Pedrazzi G, Bozzetti C, Lagrasta C, Gardini G, Tamagnini I, Bisagni A, Azzoni C, Bottarelli L, Graiani G, Romano I, Porzio R, Bacchini GP, Paties C, Tomasello G, Marchetti G, Fanello S, Pinto C, Sala R, Ardizzoni A. Strong Notch activation hinders bevacizumab efficacy in advanced colorectal cancer. Future Oncol 2015; 11:3167-74. [PMID: 26552022 DOI: 10.2217/fon.15.218] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
AIM To assess the role of Notch activation in predicting bevacizumab efficacy in colorectal cancer (CRC). MATERIALS & METHODS Notch activation was evaluated by immunohistochemistry (IHC) on 65 CRC enrolled within randomized clinical trials assessing first-line bevacizumab-based chemotherapy and on 21 CRC treated with chemotherapy alone. RESULTS Strong Notch (IHC 3+) activation was negatively associated with response (18 vs 62% in low Notch cases [IHC 0, 1, 2+]; p = 0.016), progression-free survival (4.9 vs 12.1 months; p = 0.002) and overall survival (19.3 vs 30.4 months; p = 0.039). No correlation was found between Notch activation and clinical outcome in CRC treated with chemotherapy alone. CONCLUSION A potential role of Notch activation in the antitumor activity of bevacizumab could be hypothesized.
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Affiliation(s)
- Francesca V Negri
- Medical Oncology Unit, University Hospital, Via Gramsci 14, 43126 Parma, Italy
| | - Pellegrino Crafa
- Department of Pathology, University Hospital, Via Gramsci 14, 43126 Parma, Italy
| | - Giuseppe Pedrazzi
- Department of Neuroscience, University of Parma, Via Volturno 39, 43126 Parma, Italy
| | - Cecilia Bozzetti
- Medical Oncology Unit, University Hospital, Via Gramsci 14, 43126 Parma, Italy
| | - Costanza Lagrasta
- Department of Pathology, University Hospital, Via Gramsci 14, 43126 Parma, Italy
| | - Giorgio Gardini
- Pathology Unit, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), Santa Maria Nuova Hospital, Viale Umberto I 50, 42123 Reggio Emilia, Italy
| | - Ione Tamagnini
- Pathology Unit, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), Santa Maria Nuova Hospital, Viale Umberto I 50, 42123 Reggio Emilia, Italy
| | - Alessandra Bisagni
- Pathology Unit, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), Santa Maria Nuova Hospital, Viale Umberto I 50, 42123 Reggio Emilia, Italy
| | - Cinzia Azzoni
- Department of Pathology, University Hospital, Via Gramsci 14, 43126 Parma, Italy
| | - Lorena Bottarelli
- Department of Pathology, University Hospital, Via Gramsci 14, 43126 Parma, Italy
| | - Gallia Graiani
- Department of Pathology, University Hospital, Via Gramsci 14, 43126 Parma, Italy
| | - Ida Romano
- Department of Radiology, University Hospital, Via Gramsci 14, 43126 Parma, Italy
| | - Rosa Porzio
- Medical Oncology Unit, Azienda Unità Sanitaria Locale, Via Taverna 49, 29121 Piacenza, Italy
| | - Gian P Bacchini
- Medical Oncology Unit, University Hospital, Via Gramsci 14, 43126 Parma, Italy
| | - Carlo Paties
- Pathology Unit, Azienda Unità Sanitaria Locale, Via Taverna 49, 29121 Piacenza, Italy
| | - Gianluca Tomasello
- Medical Oncology Unit, Azienda Istituti Ospitalieri, Viale Concordia 1, 26100 Cremona, Italy
| | - Giovanni Marchetti
- Pathology Unit, Azienda Ospedaliera S.Maria Terni, Viale Tristano di Joannuccio 1, 05100 Terni, Italy
| | - Silvia Fanello
- Medical Oncology Unit, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), Santa Maria Nuova Hospital, Viale Umberto I 50, 42123 Reggio Emilia, Italy
| | - Carmine Pinto
- Medical Oncology Unit, University Hospital, Via Gramsci 14, 43126 Parma, Italy
| | - Roberto Sala
- Department of Biomedical Biotechnological & Translational Sciences (S.Bi.Bi.T), University of Parma, Via Volturno 39, 43126 Parma, Italy
| | - Andrea Ardizzoni
- Medical Oncology Unit, St Orsola-Malpighi Hospital, Via Albertoni 15, 40138 Bologna, Italy
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Grapsa D, Syrigos K, Saif MW. Bevacizumab in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy for first-line and maintenance treatment of metastatic colorectal cancer. Expert Rev Anticancer Ther 2015; 15:1267-81. [PMID: 26506906 DOI: 10.1586/14737140.2015.1102063] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Despite a slight decrease in mortality rates, recent advances in screening methods, diagnosis and overall improved therapeutic options, colorectal cancer (CRC) remains among the leading causes of cancer-related death worldwide. The major cause is the mortality related to metastatic status of CRC. Increasing clinical evidence derived from randomized trials strongly suggests that the efficacy of standard cytotoxic agents, including various combinations of 5-fluoouracil (5-FU)/leucovorin (LV), capecitabine, irinotecan and oxaliplatin, may be significantly augmented with concomitant administration of molecular agents targeting the vascular endothelial growth factor (VEGF) signaling pathways, such as bevacizumab. Herein, we critically discuss the current data on the efficacy and safety profile of bevacizumab in combination with fluoropyrimidine-based chemotherapy for first-line and maintenance treatment of metastatic CRC and briefly comment on existing controversies and future perspectives.
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Affiliation(s)
- Dimitra Grapsa
- a Oncology Unit, 3rd Department of Medicine, "Sotiria" General Hospital , Athens University School of Medicine , Athens , Greece
| | - Konstantinos Syrigos
- a Oncology Unit, 3rd Department of Medicine, "Sotiria" General Hospital , Athens University School of Medicine , Athens , Greece
| | - Muhammad Wasif Saif
- a Oncology Unit, 3rd Department of Medicine, "Sotiria" General Hospital , Athens University School of Medicine , Athens , Greece
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20
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Ghiringhelli F, Vincent J, Beltjens F, Bengrine L, Ladoire S. Fluorouracil, leucovorin and irinotecan associated with aflibercept can induce microscopic colitis in metastatic colorectal cancer patients. Invest New Drugs 2015; 33:1263-6. [PMID: 26490656 DOI: 10.1007/s10637-015-0295-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2015] [Accepted: 10/13/2015] [Indexed: 12/22/2022]
Abstract
Aflibercept is a recombinant fusion protein that acts as a soluble decoy receptor for vascular endothelial growth factor (VEGF). This molecule binds to all isoforms of VEGF-A as well as VEGF-B and placental growth factor, preventing them from activating their respective receptors. Aflibercept is used for the treatment of metastatic colorectal cancer (mCRC) in association with irinotecan. For reasons that remain to be elucidated, the addition of aflibercept to irinotecan-based chemotherapy increases the incidence of grade 3-4 diarrhea. We performed systematic colonic biopsies in three patients with grade 3 diarrhea after introduction of fluorouracil, leucovorin, irinotecan and aflibercept treatment for mCRC. For each patient, the diarrhea necessitated treatment discontinuation. Colonoscopy showed normal colonic mucosa. However, histopathological examination of the biopsies performed in these three patients revealed typical features of microscopic colitis. All three patients were treated with budesonide and mesalazine, leading to rapid regression of clinical symptoms. Chemotherapy was reintroduced in all patients, with only mild, grade 1 diarrhea under mesalazine and budesonide treatment. These are the first observations of aflibercept-induced microscopic colitis, and support the use of specific treatment on top of anti-diarrheal treatment in case of important digestive adverse events.
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Affiliation(s)
- François Ghiringhelli
- INSERM UMR866, Dijon, France. .,Faculté de Médecine, Université de Bourgogne, Dijon, France. .,Department of Medical Oncology, Centre Georges François Leclerc, 1 rue du Professeur Marion, 21000, Dijon, France.
| | - Julie Vincent
- Department of Medical Oncology, Centre Georges François Leclerc, 1 rue du Professeur Marion, 21000, Dijon, France
| | | | - Leila Bengrine
- Department of Medical Oncology, Centre Georges François Leclerc, 1 rue du Professeur Marion, 21000, Dijon, France
| | - Sylvain Ladoire
- INSERM UMR866, Dijon, France. .,Faculté de Médecine, Université de Bourgogne, Dijon, France. .,Department of Medical Oncology, Centre Georges François Leclerc, 1 rue du Professeur Marion, 21000, Dijon, France.
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21
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Rosa B, de Jesus JP, de Mello EL, Cesar D, Correia MM. Effectiveness and safety of monoclonal antibodies for metastatic colorectal cancer treatment: systematic review and meta-analysis. Ecancermedicalscience 2015; 9:582. [PMID: 26557880 PMCID: PMC4631576 DOI: 10.3332/ecancer.2015.582] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2015] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The effectiveness of chemotherapy (CT) for select cases of metastatic colorectal cancer (MCRC) has been well established in the literature, however, it provides limited benefits and in many cases constitutes a treatment with high toxicity. The use of specific molecular biological treatments with monoclonal antibodies (MA) has been shown to be relevant, particularly for its potential for increasing the response rate of the host to the tumour, as these have molecular targets present in the cancerous cells and their microenvironment thereby blocking their development. The combination of MA and CT can bring a significant increase in the rate of resectability of metastases, the progression-free survival (PFS), and the global survival (GS) in MCRC patients. OBJECTIVE To assess the effectiveness and safety of MA in the treatment of MCRC. METHODS A systematic review was carried out with a meta-analysis of randomised clinical trials comparing the use of cetuximab, bevacizumab, and panitumumab in the treatment of MCRC. RESULTS Sixteen randomised clinical trials were selected. The quality of the evidence on the question was considered moderate and data from eight randomised clinical trials were included in this meta-analysis. The GS and PFS were greater in the groups which received the MA associated with CT, however, the differences were not statistically significant between the groups (mean of 17.7 months versus 17.1 months; mean difference of 1.09 (CI: 0.10-2.07); p = 0.84; and 7.4 versus 6.9 months. mean difference of 0.76 (CI: 0.08-1.44); p = 0.14 respectively). The meta-analysis was not done for any of the secondary outcomes. CONCLUSION The addition of MA to CT for patients with metastatic colorectal cancer does not prolong GS and PFS.
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Affiliation(s)
- Bruno Rosa
- Instituto Nacional de Câncer, Rio de Janeiro 20230-130, Brazil
| | | | | | - Daniel Cesar
- Instituto Nacional de Câncer, Rio de Janeiro 20230-130, Brazil
| | - Mauro M Correia
- Instituto Nacional de Câncer, Rio de Janeiro 20230-130, Brazil
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22
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Kubáčková K, Bortlíček Z, Pikus T, Linke Z, Pokorná P, Vyzula R, Prausová J. Bevacizumab with chemotherapy in patients with KRAS wild-type metastatic colorectal cancer: Czech registry data. Future Oncol 2015; 11:225-32. [PMID: 25591837 DOI: 10.2217/fon.14.240] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
AIM This retrospective analysis investigated the effectiveness of combination therapy with bevacizumab and chemotherapy in the first-line treatment of patients with KRAS wild-type metastatic colorectal cancer. PATIENTS & METHODS Patients with KRAS wild-type metastatic colorectal cancer in the CORECT registry who initiated treatment with bevacizumab between 2008 and 2012 were enrolled. Overall survival and progression-free survival were the main effectiveness end points. RESULTS A total of 981 patients were enrolled. Median progression-free survival was 11.3 months (95% CI: 10.7-11.8) and median overall survival was 28.4 months (95% CI: 26.2-30.6). The most common adverse events were thromboembolic disease (4%) and hypertension (3.5%). CONCLUSION This retrospective analysis shows the effectiveness of bevacizumab with chemotherapy in patients with KRAS wild-type metastatic colorectal cancer.
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Affiliation(s)
- Kateřina Kubáčková
- Department of Oncology, University Hospital Motol, Prague, Czech Republic
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23
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Yalcin S, Trad D, Kader YA, Halawani H, Demir OG, Mall R, Meshcheryakov A, Nasr F, Nosworthy A, Osinsky D, Tumanova A, Turhal S, Tejpar S, Köhne CH. Personalized treatment is better than one treatment fits all in the management of patients with mCRC: a consensus statement. Future Oncol 2015; 10:2643-57. [PMID: 25531050 DOI: 10.2217/fon.14.203] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The VEGF- (bevacizumab) and EGFR- (cetuximab and panitumumab) targeting monoclonal antibodies have become integral components of the first-line treatment strategies for patients with metastatic colorectal cancer (mCRC). Increasingly combination chemotherapy, with or without a targeted agent, is being used to facilitate curative liver resection and improve survival rates in patients with initially unresectable but potentially resectable mCRC. Currently, the only selective marker for the treatment of patients with mCRC is tumor RAS mutational status. BRAF status is a strong prognostic indicator. Medical and clinical oncologists from Central Asia, Russia, the Middle East, Africa and Turkey reviewed data for the use of targeted agents in the treatment of patients with mCRC and have formed recommendations for the biological of choice first-line for patients with mCRC.
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Affiliation(s)
- Suayib Yalcin
- Department of Medical Oncology, Hacettepe University Institute of Cancer, Hacettepe University, Ankara, Turkey
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24
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Bergsland EK. Is more not better?: combination therapies in colorectal cancer treatment. Hematol Oncol Clin North Am 2015; 29:85-116. [PMID: 25475574 DOI: 10.1016/j.hoc.2014.09.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The treatment of colorectal cancer has evolved dramatically in recent years with the availability of new chemotherapeutic agents and inhibitors of the vascular endothelial growth factor- and epidermal growth factor-signaling pathways. The incremental benefit of each individual line of therapy for advanced disease is relatively small. Advances in our ability to select patients should improve the cost-effectiveness of our treatment strategies (avoiding unnecessary toxicity in the patients who are unlikely to benefit and accepting the potential for adverse events in the patients who stand to benefit the most from a given regimen).
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Affiliation(s)
- Emily K Bergsland
- Department of Medicine, Division of Hematology and Oncology, UCSF Helen Diller Family Comprehensive Cancer Center, 1600 Divisadero Street, A727, San Francisco, CA 94115, USA.
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25
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Kovacevic A, Dragojevic-Simic V, Tarabar D, Rancic N, Jacimovic N, Katic J, Dagovic A, Jakovljevic M. Five-year survival and costs of care in metastatic colorectal cancer: conventional versus monoclonal antibody-based treatment protocols. Expert Rev Anticancer Ther 2015; 15:963-70. [PMID: 26089093 DOI: 10.1586/14737140.2015.1059280] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
AIM To evaluate the costs and survival estimates of metastatic colorectal carcinoma patients treated with conventional cytostatic protocols and adjuvant monoclonal antibodies (mAbs). METHODS Retrospective randomized case series and cost-of-illness analysis was used. Metastatic colorectal carcinoma cases (62) were randomly selected from the archive of the largest university military hospital in Southeastern Europe. RESULTS A 6-month longer survival was attributed to mAbs (p = 0.581). Conventional protocols incurred € 5137 (95% CI: € 3758-€ 6517) versus € 22,113 (95% CI: € 16,201-€ 28,025) total direct medical costs in mAb-based group. ICER of € 32,108 per life year gained attributable to mAbs three-fold exceeded informal willingness to pay threshold of Serbia. CONCLUSION mAbs adjuvant protocols had modest positive impact on 5-year survival rates. Costs were driven by targeted biologicals, but significantly higher costs of care were recorded in mAb-treated group in other domains, as well. More selective prescription and reimbursement criteria should be applied to increase cost-effectiveness of targeted oncology agents.
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Affiliation(s)
- Aleksandra Kovacevic
- Centre for Clinical Pharmacology, Military Medical Academy Medical Faculty, University of Defense, Belgrade, Serbia, Europe
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26
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Salgado Fernández M, Pérez Hoyos MT, Díaz de Corcuera I, Vidal Arbués A, García de la Torre M. Aflibercept for metastatic colorectal cancer: safety data from the Spanish named patient program. Expert Opin Drug Saf 2015; 14:1171-9. [PMID: 26076885 DOI: 10.1517/14740338.2015.1057495] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
OBJECTIVE Aflibercept increased overall survival with acceptable tolerability in metastatic colorectal cancer (mCRC) when it was used in combination with FOLFIRI after progression on a first-line oxaliplatin regimen (VELOUR study). The safety profile of aflibercept in day-to-day clinical practice was assessed. DESIGN AND METHODS A named patient program provided early access to aflibercept to mCRC patients in Spain before its commercialization. Patients received aflibercept 4 mg/kg intravenous + FOLFIRI every 2 weeks as second-line treatment. A descriptive safety analysis was conducted. RESULTS Data from 89 mCRC patients were analyzed (male: 61.8%; median age: 62 years [interquartile range: 55, 67]; Eastern Cooperative Oncology Group 0 - 1: 95.5%). Fifty four (60.7%) patients presented ≥ 2 metastasis [liver (83.1%), lung (44.9%) or lymph nodes (33.7%)]. Most patients had previously received bevacizumab (60.7%) or anti-EGFR (19.1%) therapy. Patients received a median of 6.0 (interquartile range: 4, 13) cycles of FOLFIRI + aflibercept. Most grade ≥ 3 adverse events (AEs) were reported during the initial cycles of treatment. AEs possibly related to treatment occurred in 39 (43.8%) patients. Common grade ≥ 3 treatment-related AEs were neutropenia (7.9%), diarrhea (4.5%) and hypertension (3.4%). CONCLUSIONS In clinical practice, aflibercept + FOLFIRI is well tolerated, with a manageable toxicity profile. The safety results confirm the findings from the confirmatory VELOUR trial.
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Affiliation(s)
- Mercedes Salgado Fernández
- Oncología Médica, Complexo Hospitalario Universitario de Ourense, C/Ramon Puga Noguerol , 52-54, 32005 Ourense , Spain +34 9 8838 5471 ; +34 9 8838 5398 ;
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27
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Krebs MG, Renehan AG, Backen A, Gollins S, Chau I, Hasan J, Valle JW, Morris K, Beech J, Ashcroft L, Saunders MP, Dive C. Circulating Tumor Cell Enumeration in a Phase II Trial of a Four-Drug Regimen in Advanced Colorectal Cancer. Clin Colorectal Cancer 2015; 14:115-22.e1-2. [PMID: 25680623 DOI: 10.1016/j.clcc.2014.12.006] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Revised: 12/16/2014] [Accepted: 12/19/2014] [Indexed: 01/11/2023]
Abstract
BACKGROUND Multidrug regimens are active against advanced colorectal cancer (ACRC). However, the increased toxicity requires the use of biomarkers to select the patients who will derive the most benefit. We assessed circulating tumor cells (CTCs) as a prognostic biomarker in patients treated with a 4-drug regimen. PATIENTS AND METHODS A single-arm phase II trial (Erbitux Study of CPT11, Oxaliplatin, UFToral Targeted-therapy [eSCOUT]) was undertaken in patients with previously untreated KRAS wild-type ACRC using a regimen of irinotecan, oxaliplatin, and tegafur-uracil with leucovorin and cetuximab. Baseline CTCs were enumerated using CellSearch. The endpoints were an objective response rate (ORR) and overall survival (OS). We modeled our results and compared them with those modeled for the capecitabine, oxaliplatin, bevacizumab +/- cetuximab (CAIRO2) trial, stratifying patients a priori into low (< 3) and high (≥ 3) CTC groups. RESULTS For 48 eligible patients, the best ORR from the 4-drug regimen was 71%, with a disease control rate of 98%. The median OS for patients with a high and low CTC count was 18.7 and 22.3 months (log-rank test, P = .038), respectively. In our modeled data, for patients with a low CTC count, no differences were found between the median OS in the eSCOUT trial and that in the CAIRO2 trial (22.2 vs. 22.0 months). However, for the high CTC group, a clinically relevant improvement was seen in median OS (eSCOUT vs. CAIRO2, 18.7 vs. 13.7 months; P = .001). CONCLUSION These data are hypothesis generating-for patients with ACRC, stratification by CTC count can identify those who might benefit the most from an intensive 4-drug regimen, avoiding high-toxicity regimens in low CTC groups. This hypothesis warrants validation in a phase III biomarker-driven trial.
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Affiliation(s)
- Matthew G Krebs
- Clinical and Experimental Pharmacology, Cancer Research UK Manchester Institute, Manchester, UK; The Christie NHS Foundation Trust, Manchester, UK; Institute of Cancer Sciences, University of Manchester, Manchester, UK
| | - Andrew G Renehan
- Clinical and Experimental Pharmacology, Cancer Research UK Manchester Institute, Manchester, UK; Institute of Cancer Sciences, University of Manchester, Manchester, UK
| | - Alison Backen
- Clinical and Experimental Pharmacology, Cancer Research UK Manchester Institute, Manchester, UK
| | | | - Ian Chau
- The Royal Marsden Hospital, London, UK
| | | | - Juan W Valle
- The Christie NHS Foundation Trust, Manchester, UK; Institute of Cancer Sciences, University of Manchester, Manchester, UK
| | - Karen Morris
- Clinical and Experimental Pharmacology, Cancer Research UK Manchester Institute, Manchester, UK
| | | | | | | | - Caroline Dive
- Clinical and Experimental Pharmacology, Cancer Research UK Manchester Institute, Manchester, UK
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Yamaue H, Tsunoda T, Tani M, Miyazawa M, Yamao K, Mizuno N, Okusaka T, Ueno H, Boku N, Fukutomi A, Ishii H, Ohkawa S, Furukawa M, Maguchi H, Ikeda M, Togashi Y, Nishio K, Ohashi Y. Randomized phase II/III clinical trial of elpamotide for patients with advanced pancreatic cancer: PEGASUS-PC Study. Cancer Sci 2015; 106:883-90. [PMID: 25867139 PMCID: PMC4520640 DOI: 10.1111/cas.12674] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Revised: 04/01/2015] [Accepted: 04/08/2015] [Indexed: 12/15/2022] Open
Abstract
Gemcitabine is a key drug for the treatment of pancreatic cancer; however, with its limitation in clinical benefits, the development of another potent therapeutic is necessary. Vascular endothelial growth factor receptor 2 is an essential target for tumor angiogenesis, and we have conducted a phase I clinical trial using gemcitabine and vascular endothelial growth factor receptor 2 peptide (elpamotide). Based on the promising results of this phase I trial, a multicenter, randomized, placebo-controlled, double-blind phase II/III clinical trial has been carried out for pancreatic cancer. The eligibility criteria included locally advanced or metastatic pancreatic cancer. Patients were assigned to either the Active group (elpamotide + gemcitabine) or Placebo group (placebo + gemcitabine) in a 2:1 ratio by the dynamic allocation method. The primary endpoint was overall survival. The Harrington–Fleming test was applied to the statistical analysis in this study to evaluate the time-lagged effect of immunotherapy appropriately. A total of 153 patients (Active group, n = 100; Placebo group, n = 53) were included in the analysis. No statistically significant differences were found between the two groups in the prolongation of overall survival (Harrington–Fleming P-value, 0.918; log–rank P-value, 0.897; hazard ratio, 0.87, 95% confidence interval [CI], 0.486–1.557). Median survival time was 8.36 months (95% CI, 7.46–10.18) for the Active group and 8.54 months (95% CI, 7.33–10.84) for the Placebo group. The toxicity observed in both groups was manageable. Combination therapy of elpamotide with gemcitabine was well tolerated. Despite the lack of benefit in overall survival, subgroup analysis suggested that the patients who experienced severe injection site reaction, such as ulceration and erosion, might have better survival. Phase II/III trial of elpamotide was performed to evaluate the clinical effect for advanced pancreatic cancer. Despite the lack of benefit in OS, sub-group analysis suggested that the patients with severe ISR might have better survival.
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Affiliation(s)
- Hiroki Yamaue
- Second Department of Surgery Wakayama Medical University, Wakayama, Japan
| | - Takuya Tsunoda
- Second Department of Surgery Wakayama Medical University, Wakayama, Japan
| | - Masaji Tani
- Second Department of Surgery Wakayama Medical University, Wakayama, Japan
| | - Motoki Miyazawa
- Second Department of Surgery Wakayama Medical University, Wakayama, Japan
| | - Kenji Yamao
- Department of Gastroenterology Aichi Cancer Center Hospital, Aichi, Japan
| | - Nobumasa Mizuno
- Department of Gastroenterology Aichi Cancer Center Hospital, Aichi, Japan
| | - Takuji Okusaka
- Hepatobiliary and Pancreatic Oncology Division National Cancer Center Hospital, Tokyo, Japan
| | - Hideki Ueno
- Hepatobiliary and Pancreatic Oncology Division National Cancer Center Hospital, Tokyo, Japan
| | - Narikazu Boku
- Department of Gastroenterology Shizuoka Cancer Center, Shizuoka, Japan
| | - Akira Fukutomi
- Department of Gastroenterology Shizuoka Cancer Center, Shizuoka, Japan
| | - Hiroshi Ishii
- Hepatobiliary and Pancreatic Division Cancer Institute Hospital, Tokyo, Japan
| | - Shinichi Ohkawa
- Hepatobiliary and Pancreatic Medical Oncology Division Kanagawa Cancer Center Hospital, Kanagawa, Japan
| | - Masayuki Furukawa
- Department of Gastroenterology National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan
| | - Hiroyuki Maguchi
- Center for Gastroenterology Teine-Keijinkai Hospital, Hokkaido, Japan
| | - Masafumi Ikeda
- Division of Hepatobiliary and Pancreatic Oncology National Cancer Center Hospital East, Chiba, Japan
| | - Yosuke Togashi
- Dept Genome Biology Kinki University School of Medicine, Osaka, Japan
| | - Kazuto Nishio
- Dept Genome Biology Kinki University School of Medicine, Osaka, Japan
| | - Yasuo Ohashi
- Department of Integrated Science and Engineering for Sustainable society Chuo University, Tokyo, Japan
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29
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Ruff P, Ferry DR, Lakomỳ R, Prausová J, Van Hazel GA, Hoff PM, Cunningham D, Arnold D, Schmoll HJ, Moiseyenko VM, McKendrick JJ, Ten Tije AJ, Vishwanath RL, Bhargava P, Chevalier S, Macarulla T, Van Cutsem E. Time course of safety and efficacy of aflibercept in combination with FOLFIRI in patients with metastatic colorectal cancer who progressed on previous oxaliplatin-based therapy. Eur J Cancer 2014; 51:18-26. [PMID: 25466509 DOI: 10.1016/j.ejca.2014.10.019] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2014] [Revised: 08/12/2014] [Accepted: 10/23/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND Patients with metastatic colorectal cancer (mCRC) previously-treated with oxaliplatin benefit significantly from the addition of aflibercept to FOLFIRI in relation to overall survival, progression-free survival and response rate. PATIENTS AND METHODS The results for efficacy and safety over the time course of the VEGF Trap (aflibercept) with irinotecan in colorectal cancer after failure of oxaliplatin regimen trial were analysed based on data from 1226 patients randomised to receive FOLFIRI plus either aflibercept (n=612) or placebo (n=614). Hazard ratios (HR) by 6-month time period were estimated using a piecewise Cox proportional hazard model. Severity of adverse events (AEs) was graded using National Cancer Institute Common Terminology Criteria, version 3.0. RESULTS The estimated probabilities of survival were 38.5% versus 30.9% at 18 months, 28.0% versus 18.7% at 24 months and 22.3% versus 12.0% at 30 months, for the aflibercept- and placebo-treated arms, respectively. The proportional improvement in the HR over time was consistent with the survival probability results; survival at 24 months was improved by 50% and almost doubled at 30 months. The majority of worst-grade AEs occurred within the first four cycles of treatment and in a small percent of treatment cycles and were mostly reversible. Common chemotherapy- and anti-vascular epithelial growth factor (VEGF)-associated AEs occurred rarely and in a small proportion of cycles with the majority being of single occurrence. CONCLUSIONS The addition of aflibercept to FOLFIRI showed a continued and persistent improvement in overall survival over time in patients with mCRC. Although grade 3-4 AEs were more frequent in the aflibercept arm, they occurred in early treatment cycles and decreased sharply following initial presentation.
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Affiliation(s)
- Paul Ruff
- University of Witwatersrand, Faculty of Health Sciences, Johannesburg, South Africa.
| | | | - Radek Lakomỳ
- Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | | | - Guy A Van Hazel
- University of Western Australia, Western Australia, Australia
| | - Paulo M Hoff
- Centro De Oncologia/Hospital Sirio Libanes, São Paulo, Brazil
| | | | - Dirk Arnold
- Department of Medical Oncology, Tumor Biology Center, Freiburg, Germany
| | | | | | | | | | | | - Pankaj Bhargava
- Sanofi Global Oncology Research and Development, Cambridge, MA, United States
| | | | - Teresa Macarulla
- Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain
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Ewara E, Zaric G, Welch S, Sarma S. Cost-effectiveness of first-line treatments for patients with KRAS wild-type metastatic colorectal cancer. Curr Oncol 2014; 21:e541-50. [PMID: 25089105 PMCID: PMC4117621 DOI: 10.3747/co.21.1837] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Combinations of chemotherapy regimens and monoclonal antibodies have been demonstrated to improve clinical outcomes in patients with metastatic colorectal cancer (mcrc). Although these combination treatment strategies are safe and effective in first-line treatment for mcrc, little is known about their economic consequences and resource allocation implications. In the present study, we evaluated the cost-effectiveness of bevacizumab plus folfiri, cetuximab plus folfiri, and panitumumab plus folfiri for patients with KRAS wild-type mcrc. METHODS A Markov model simulated the lifetime patient outcomes and costs of each first-line treatment strategy and subsequent lines of treatment from the perspective of the health care payer in Ontario. The model was parameterized using data from the Ontario Cancer Registry, Ontario health administrative databases, and published randomized control trials. Patient outcomes were measured in quality-adjusted life years (qalys), and costs were measured in monetary terms. Costs and outcomes were both discounted at 5% and expressed in 2012 Canadian dollars. RESULTS For mcrc patients with KRAS wild-type disease, the treatment strategy of bevacizumab plus folfiri was found to dominate the other two first-line treatment strategies. Sensitivity analyses revealed that the incremental cost-effectiveness ratio values were sensitive to the effectiveness of treatment, the costs of bevacizumab and cetuximab, and health utility values. CONCLUSIONS Evidence from Ontario showed that bevacizumab plus folfiri is the cost-effective first-line treatment strategy for patients with KRAS wild-type mcrc. The panitumumab plus folfiri and cetuximab plus folfiri options were both dominated, but the cetuximab plus folfiri strategy must be further investigated given that, in the sensitivity analyses, the cost-effectiveness of that strategy was found to be superior to that of bevacizumab plus folfiri under certain ranges of parameter values.
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Affiliation(s)
- E.M. Ewara
- Department of Epidemiology and Biostatistics, Schulich School of Medicine and Dentistry, Western University, London, ON
| | - G.S. Zaric
- Department of Epidemiology and Biostatistics, Schulich School of Medicine and Dentistry, Western University, London, ON
- Richard Ivey School of Business, Western University, London, ON
| | - S. Welch
- Division of Medical Oncology, Department of Oncology, Western University, London, ON
| | - S. Sarma
- Department of Epidemiology and Biostatistics, Schulich School of Medicine and Dentistry, Western University, London, ON
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Osterlund P, Peltonen R, Alanko T, Bono P, Isoniemi H. A single-institution experience with bevacizumab in the treatment of metastatic colorectal cancer and in conjunction with liver resection. Onco Targets Ther 2014; 7:1177-84. [PMID: 25061319 PMCID: PMC4085307 DOI: 10.2147/ott.s63739] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Bevacizumab is active in the treatment of metastatic colorectal cancer (mCRC). However, efficacy of bevacizumab has predominantly been evaluated on selected patients with relatively good performance status and minor comorbidities. We evaluated the efficacy and safety of bevacizumab in unselected patients with mCRC, some of whom underwent liver resection. MATERIAL AND METHODS All patients with inoperable mCRC, fit for combination chemotherapy (n=180), who were initially not resectable, not included into studies and without contraindications to bevacizumab, and initiated on bevacizumab at the Helsinki University Central Hospital between April 2004 and December 2005 were included (n=114). Most (n=70) received 5-fluorouracil/leucovorin/irinotecan plus bevacizumab as first-line therapy. The remainder (n=44) of the patients received bevacizumab in combination with oxaliplatin or irinotecan with or without 5-fluorouracil or capecitabine. Minimum follow-up was 7 years. Treatment response was evaluated every 8-10 weeks according to RECIST criteria. RESULTS Median age was 59.6 years (range 35-79); male/female ratio was 54%/46%; World Health Organization performance status 0/1/2-3 was 33%/55%/11%, respectively; and the number of metastatic sites, one/two/three or more, was 31%/21%/48%, respectively. Median duration of bevacizumab therapy was 7.8 months (range 0.5-70.5 with pauses). In first-line (n=40), response rate (RR) was 62%, progression-free survival (PFS) 11.7 months, and overall survival (OS) 22.1 months. In second-line (n=43), RR was 44%, PFS 8.7 months, and OS 18.7 months. In later lines (n=31), RR was 14%, PFS 6.7 months, and OS 14.2 months. Ten patients with initially unresectable liver metastases became operable and R0 resection was achieved in 90% (9/10 resections). In 23% (7/31) of operated metastases, no vital tumor cells were found in histologic examination. Operative morbidity was low: two mild infections, no increased bleeding tendency was noticed, and no impaired wound healing occurred. DISCUSSION Bevacizumab-containing combination therapy was effective with acceptable tolerability in an unselected mCRC patient population in which liver resections could be safely performed.
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Affiliation(s)
- Pia Osterlund
- Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland
- Institute of Clinical Medicine, University of Helsinki, Helsinki, Finland
| | - Reetta Peltonen
- Institute of Clinical Medicine, University of Helsinki, Helsinki, Finland
- Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland
| | - Tuomo Alanko
- Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland
| | - Petri Bono
- Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland
- Institute of Clinical Medicine, University of Helsinki, Helsinki, Finland
| | - Helena Isoniemi
- Institute of Clinical Medicine, University of Helsinki, Helsinki, Finland
- Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland
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The role of antiangiogenic agents in the treatment of patients with advanced colorectal cancer according to K-RAS status. Angiogenesis 2014; 17:805-21. [PMID: 24793846 DOI: 10.1007/s10456-014-9433-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2012] [Accepted: 04/21/2014] [Indexed: 12/30/2022]
Abstract
Colorectal cancer (CRC) is the fourth most commonly diagnosed cancer worldwide. Recently, it has been found that about 40 % of patients with CRC have mutations in the K-RAS gene. Several clinical trials have showed that patients with metastatic colorectal cancer (mCRC) who present tumour-promoting mutations in signalling pathways involving the epidermal growth factor receptor (EGFR), which includes activating K-RAS mutations, do not respond to anti-EGFR drugs such as panitumumab and cetuximab. Hence, K-RAS status is now considered an important negative predictive factor for response to anti-EGFR drugs. Moreover, K-RAS status seems to have also a prognostic role in CRC, but this fact is somewhat controversial. Activity of antiangiogenic agents seems not to be influenced by K-RAS gene status. Tumour angiogenesis has attracted interest in attempts to improve the management of mCRC. The vascular endothelial growth factor (VEGF) pathway is fundamental to the regulation of angiogenesis, and research has focused on developing agents that selectively target it. In this way, the anti-VEGF antibody bevacizumab in combination with chemotherapy has provided important clinical benefits in terms of response rate, progression-free survival and overall survival to patients with mCRC. Efficacy data of bevacizumab in K-RAS wild-type patients seem to be comparable with the efficacy data observed with anti-EGFR therapies in a cross-trial comparison. Although there is a lack of prospective and randomized data in this setting, the combination of chemotherapy plus antiangiogenic agents could be considered as an effective alternative for the treatment of mCRC with independence of K-RAS gene status. Here, we review the available data we have in the literature of the use of antiangiogenic strategies in the treatment of mCRC nowadays.
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Temraz S, Mukherji D, Shamseddine A. Sequencing of treatment in metastatic colorectal cancer: where to fit the target. World J Gastroenterol 2014; 20:1993-2004. [PMID: 24616571 PMCID: PMC3934469 DOI: 10.3748/wjg.v20.i8.1993] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Revised: 12/01/2013] [Accepted: 01/14/2014] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer is a lethal disease if not discovered early. Even though appropriate screening and preventive strategies are in place in many countries, a significant number of patients are still diagnosed at late stages of the disease. The management of metastatic colorectal cancer remains a significant clinical challenge to oncologists worldwide. While cytotoxic regimens constitute the main treatment of choice in this patient population, addition of the five biologics (bevacizumab, cetuximab, aflibercept, panitumumab and regorafenib) to these regimens has improved clinical outcomes. The most commonly used cytotoxic regimens include doublet combinations (FOLFOX/XELOX or FOLFIRI). Many clinical trials have been published and others are underway to compare the biologic agents with one another in order to prove the superiority of one regimen over another. Metastatic colorectal cancer patients have many treatment options; however, the optimal use and sequence of targeted agents remain to be determined. This review entails concise and updated clinical data on the management of metastatic colorectal cancer. The aim of the review is to determine where to fit the five biologic targets into the treatment algorithm of metastatic colorectal cancer patients and to derive treatment sequences that would achieve best clinical outcome based on the current available data.
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Grenon NN. Managing toxicities associated with antiangiogenic biologic agents in combination with chemotherapy for metastatic colorectal cancer. Clin J Oncol Nurs 2014; 17:425-33. [PMID: 23899982 DOI: 10.1188/13.cjon.425-433] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Toxicities commonly associated with antiangiogenic agents include hypertension, proteinuria, wound-healing complications, bleeding or hemorrhage, thromboembolic events, hypersensitivity reactions, and gastrointestinal perforation; however, toxicities most often attributed to chemotherapy include nausea, vomiting, diarrhea, constipation, fatigue, neuropathy, mucositis, hand-foot syndrome, hypersensitivity reactions, and myelosuppression. Patients with metastatic colorectal cancer (mCRC) who receive an antiangiogenic agent in combination with chemotherapy may experience toxicities related to both chemotherapy and the antiangiogenic agent. If possible, evidence-based interventions should be used for the management of toxicities. Patient education about expected toxicities and optimal toxicity management can promote the optimal use of therapy to improve survival and quality of life. Oncology nurses are well positioned to educate patients and their families on anticipated treatment and management of side effects. This article summarizes the incidence of toxicities associated with the antiangiogenic biologic agents aflibercept and bevacizumab, in combination with chemotherapy for patients with mCRC, and provides strategies for managing these toxicities based on clinical practice guidelines.
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Amadio A, Burkes R, Bailie T, McLean M, Coleman B. Impact of granulocyte colony-stimulating factors in metastatic colorectal cancer patients. ACTA ACUST UNITED AC 2014; 21:e52-61. [PMID: 24523621 DOI: 10.3747/co.21.1645] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND Delays in chemotherapy because of neutropenia may be associated with poorer outcomes. The purpose of the present study was to examine the effect that granulocyte colony-stimulating factors (g-csfs) have on survival. METHODS We conducted a chart review of all outpatients diagnosed with metastatic colorectal cancer and treated with folfiri chemotherapy (irinotecan, 5-fluorouracil, leucovorin) with or without bevacizumab at Mount Sinai Hospital between 2007 and 2012. Multivariable Cox proportional hazards models were used to compare survival in neutropenic patients treated with g-csf, in neutropenic patients not so treated, and in patients without neutropenia. RESULTS The review identified 93 patients, 31 of whom did not experience a neutropenic event. Of the 62 who experienced neutropenia, 18 were managed with g-csf support, and 44, with reductions or delays in dose. Compared with patients experiencing a neutropenic episode not treated with g-csf, those treated with g-csf experienced a nonsignificant increase in time to event [progression or death: hazard ratio (hr): 1.37; 95% confidence limits (cl): 0.72, 2.61], but compared with patients not having a neutropenic episode, the same patients experienced a significant increase in time to event (hr: 2.07; 95% cl: 1.03, 4.15). CONCLUSIONS In patients who experienced neutropenia, g-csf did not have a statistically significant impact on survival. Time to event was prolonged in g-csf-treated patients compared with patients who did not experience neutropenia.
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Affiliation(s)
- A Amadio
- Department of Pharmacy, Mount Sinai Hospital, Toronto, ON
| | - R Burkes
- Department of Oncology, Mount Sinai Hospital, Toronto, ON
| | - T Bailie
- Department of Pharmacy, Mount Sinai Hospital, Toronto, ON
| | - M McLean
- Department of Pharmacy, Mount Sinai Hospital, Toronto, ON
| | - B Coleman
- Department of Pharmacy, Mount Sinai Hospital, Toronto, ON
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Zhu P, Gu YF, Yang BL, Lin Q, Ding YJ. Effects of gamboge in an orthotopic mouse model of colon cancer. Shijie Huaren Xiaohua Zazhi 2014; 22:476-482. [DOI: 10.11569/wcjd.v22.i4.476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the antitumor and anti-metastatic effects of gamboge in an orthotopic mouse model developed with human colon cancer cell line HCT116.
METHODS: A colon cancer model was developed by surgical orthotopic implantation of green fluorescent protein (GFP)-expressing HCT 116 tumor in nude mice. Forty mice were equally randomized into four groups. Group 1 served as a negative control and received intragastric infusion of normal saline once daily. Group 2 received intraperitoneal injection of 5-fluorouracil at a dose of 25 mg/kg three times per week. Groups 3 and 4 received intragastric infusion of gamboge extract at a dose of 10 and 20 mg/kg, respectively, once daily. Each animal was checked for mortality and signs of morbidity every day. Primary tumor volume and metastasis for each animal were observed under a fluorescence imaging system twice a week, and body weights were measured as well. At the end of the experiment, all mice were sacrificed and open fluorescent images of tumors and metastases expressing GFP were acquired, and the tumor was removed from each mouse and weighed.
RESULTS: After initiation of different treatment regimens, the average tumor volume (mm3) was significantly smaller in the gamboge (20 mg/kg) group than the control group at each observation point (d4: 104.5 ± 35.5 vs 164.1 ± 66.1; d7: 102.6 ± 53.8 vs 286.2 ± 132.0; d11: 137.6 ± 70.5 vs 324.4 ± 115.8; d14: 207.2 ± 101.7 vs 434.2 ± 169.3; d21: 229.8 ± 99.8 vs 480.4 ± 165.5; P < 0.05 for all). At the end of the study, the average tumor weight was significantly smaller in the gamboge group (20 mg/kg) than in the control group (0.58 ± 0.26 vs 0.92 ± 0.26, P < 0.05). There were no statistical differences between the gamboge (20 mg/kg) group and 5-fluorouracil group, as well as between the gamboge (10 mg/kg) group and control group, in term of average tumor volume and weight (P > 0.05 for all). At the end of the experiment, open GFP imaging demonstrated that all groups presented metastasis of lymph nodes or the pancreas, although there were no significant differences between the four groups with regard to the metastasis rate (P > 0.05 for all). No significant morbidity or weight loss was found in all tumor-bearing mice.
CONCLUSION: Gamboge at a dose of 20 mg/kg was able to suppress HCT 116 tumor growth in an orthotopic mouse model of colon cancer safely and effectively, and may possess clinical therapeutic potential for colorectal cancer.
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Suenaga M, Fuse N, Yamaguchi T, Yamanaka Y, Motomura S, Matsumoto H, Hamamoto Y, Mizunuma N, Doi T, Hatake K, Iwasaki J, Ohtsu A. Pharmacokinetics, safety, and efficacy of FOLFIRI plus bevacizumab in Japanese colorectal cancer patients with UGT1A1 gene polymorphisms. J Clin Pharmacol 2014; 54:495-502. [DOI: 10.1002/jcph.246] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2013] [Accepted: 12/02/2013] [Indexed: 11/12/2022]
Affiliation(s)
- Mitsukuni Suenaga
- Department of Gastroenterology; Cancer Institute Hospital; Tokyo Japan
| | - Nozomu Fuse
- National Cancer Center Hospital East; Kashiwa Chiba Japan
| | - Tatsuro Yamaguchi
- Department of Surgery; Tokyo Metropolitan Komagome Hospital; Tokyo Japan
| | - Yasuhiro Yamanaka
- Department of Medical Oncology; Tochigi Cancer Center; Utsunomiya Tochigi Japan
| | - Shigeki Motomura
- Department of Medical Oncology; Kanagawa Cancer Center; Yokohama Kanagawa Japan
| | - Hiroshi Matsumoto
- Department of Surgery; Tokyo Metropolitan Komagome Hospital; Tokyo Japan
| | - Yasuo Hamamoto
- Department of Medical Oncology; Tochigi Cancer Center; Utsunomiya Tochigi Japan
| | - Nobuyuki Mizunuma
- Department of Gastroenterology; Cancer Institute Hospital; Tokyo Japan
| | - Toshihiko Doi
- National Cancer Center Hospital East; Kashiwa Chiba Japan
| | - Kiyohiko Hatake
- Department of Gastroenterology; Cancer Institute Hospital; Tokyo Japan
| | - Junko Iwasaki
- Clinical Development Division; Chugai Pharmaceutical Co., Ltd; Tokyo Japan
| | - Atsushi Ohtsu
- National Cancer Center Hospital East; Kashiwa Chiba Japan
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Survival outcomes of bevacizumab in first-line metastatic colorectal cancer in a real-life setting: results of the ETNA cohort. Target Oncol 2013; 9:311-9. [DOI: 10.1007/s11523-013-0296-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2013] [Accepted: 10/30/2013] [Indexed: 12/19/2022]
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Abstract
PURPOSE Important developments in chemotherapy for advanced colorectal cancer over the past 15 years are reviewed, with an emphasis on the most recently published data from clinical trials of newer multidrug regimens, administration techniques, and dosing schedules. SUMMARY Eight agents are approved by the Food and Drug Administration (FDA) for use in treating patients with advanced colorectal cancer. Fluorouracil and leucovorin still constitute the foundation of most chemotherapy regimens for this population; combination fluorouracil-leucovorin therapy plus either irinotecan (the FOLFIRI regimen) or oxaliplatin (the FOLFOX regimen) are two firmly established first-line treatments shown to produce similar outcomes. In Phase III trials conducted over the past six to seven years, regimens of capecitabine plus oxaliplatin (CapeOx) were demonstrated to have clinical effectiveness comparable to that of FOLFOX therapy. Response rates of 35-55% and median overall survival of ≥20 months have been documented with some of the newer regimens. Research to define the optimal role of the three monoclonal antibody agents approved by FDA for use in managing advanced colorectal cancer is ongoing; bevacizumab has been shown to confer significant survival benefits when added to certain chemotherapy regimens, and other monoclonal antibodies (cetuximab and panitumumab) also appear to offer significant benefits in select patients as first- or second-line therapies. CONCLUSION Over the past 15 years, a shift toward multiagent treatment strategies including a variety of chemotherapy agents and monoclonal antibodies has yielded improved rates of response and prolonged survival among patients with advanced colorectal cancer. The CapeOx, FOLFOX, and FOLFIRI regimens are currently among the most widely used first-line treatments.
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Affiliation(s)
- Robert J Cersosimo
- School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, 360 Huntington Avenue, 206 Mugar Hall, Boston, MA 02115, USA.
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40
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Ruiz-Millo O, Albert-Mari A, Sendra-Garcia A, Jimenez-Torres NV. Comparative cost-effectiveness of bevacizumab-irinotecan-fluorouracil versus irinotecan-fluorouracil in first-line metastatic colorectal cancer. J Oncol Pharm Pract 2013; 20:341-50. [PMID: 24177355 DOI: 10.1177/1078155213508437] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
PURPOSE To evaluate the cost-effectiveness of the addition of bevacizumab to the irinotecan-fluorouracil (Douillard regimen-CPT-FUFA-) in first-line treatment of metastatic colorectal cancer in a single-institution population. METHODS Controlled, nonrandomized retrospective observational study. Treatment-naïve metastatic colorectal cancer patients received CPT-FUFA (January 2000-December 2003; control group) and bevacizumab_CPT-FUFA (January 2007-December 2010; study group). Variables related to: patient, clinical response (number of disease progression or death events, progression-free survival) and treatment (antineoplastic dose reduction, incremental cost/treated patient associated with the addition of bevacizumab). STATISTICAL ANALYSIS median progression-free survival (Kaplan-Meier method), and hazard ratio (Cox regression). Survival curves were compared (Mantel-Haenszel test). RESULTS In all, 69 patients were included: 32 (57.2 years -95%CI: 54.0-60.5-, 65.6% men) in CPT-FUFA group and 37 (68.1 years - 95%CI: 65.5-70.7-, 78.4% men) in bevacizumab_CPT-FUFA group. The disease progression or death events were 29 (90.6%) in CPT-FUFA group and 34 (91.9%) in bevacizumab_CPT-FUFA group. Median progression-free survival was 10.1 months (95%CI: 7.1-12.2) in CPT-FUFA and 11.0 months (95%CI: 7.6-12.6) in bevacizumab_CPT-FUFA (hazard ratio = 1.22; 95%CI: 0.7-2.1). Dose reductions: irinotecan and fluorouracil 11% (range: 4-20) in 5/32 (15.6%) CPT-FUFA patients and 25% (range: 8-35) in 18/37 (48.6%) bevacizumab_CPT-FUFA patients; Bevacizumab 30% (range: 4-50) in 20/37 (54.1%) bevacizumab_CPT-FUFA patients. The incremental cost associated with the addition of bevacizumab was 12,696.5 (IC95%:10,860.8-14,532.1) euros/patient. CONCLUSION The addition of bevacizumab to the irinotecan-fluorouracil regimen, does not improve progression-free survival in our study population but increases costs per treated patient. These results potentially compromise the cost-effectiveness of the Bevacizumab_CPT-FUFA regimen.
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Affiliation(s)
- Oreto Ruiz-Millo
- Pharmacy Department, Doctor Peset University Hospital, Valencia, Spain
| | | | - Ana Sendra-Garcia
- Pharmacy Department, Doctor Peset University Hospital, Valencia, Spain
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Methods of overcoming treatment resistance in colorectal cancer. Crit Rev Oncol Hematol 2013; 89:217-30. [PMID: 24075059 DOI: 10.1016/j.critrevonc.2013.08.015] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2013] [Revised: 07/28/2013] [Accepted: 08/30/2013] [Indexed: 12/25/2022] Open
Abstract
Metastatic colorectal cancer remains a lethal disease with a poor prognosis in the majority of patients. Multiple drug combinations have been developed in recent years that have significantly improved response rates and overall survival however resistance to these drugs is inevitable. Novel agents are currently being developed and participation in clinical trials should be encouraged. In the absence of other treatment options in a patient with good performance status, there is compelling evidence for re-challenging with previously administered agents in different combinations. The aim of this review is to discuss mechanisms of resistance and methods to overcome treatment resistance in patients with metastatic colorectal cancer who are refractory to 5-FU, irinotecan, oxaliplatin, cetuximab and bevacizumab therapy.
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Tysome JR, Lemoine NR, Wang Y. Update on oncolytic viral therapy - targeting angiogenesis. Onco Targets Ther 2013; 6:1031-40. [PMID: 23940420 PMCID: PMC3737009 DOI: 10.2147/ott.s46974] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Oncolytic viruses (OVs) have the ability to selectively replicate in and lyse cancer cells. Angiogenesis is an essential requirement for tumor growth. Like OVs, the therapeutic effect of many angiogenesis inhibitors has been limited, leading to the development of more effective approaches to combine antiangiogenic therapy with OVs. Angiogenesis can be targeted either directly by OV infection of vascular endothelial cells, or by arming OVs with antiangiogenic transgenes, which are subsequently expressed locally in the tumor microenvironment. In this review, we describe the development and targeting of OVs, the role of angiogenesis in cancer, and the progress made in arming viruses with antiangiogenic transgenes. Future developments required to optimize this approach are addressed.
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Affiliation(s)
- James R Tysome
- Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom ; Department of Otolaryngology, Cambridge University Hospitals, Cambridge, United Kingdom ; Sino-British Research Center for Molecular Oncology, Zhengzhou University, Zhengzhou, People's Republic of China
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Abstract
Bevacizumab is a monoclonal antibody that binds and neutralizes vascular endothelial growth factor (VEGF)-A, a key player in the angiogenesis pathway. Despite benefits of bevacizumab in cancer therapy, it is clear that the VEGF pathway is complex, involving multiple isoforms, receptors, and alternative ligands such as VEGF-B, and placental growth factor, which could enable escape from VEGF-A-targeted angiogenesis inhibition. Recently developed therapies have targeted other ligands in the VEGF pathway (eg, aflibercept, known as ziv-aflibercept in the United States), VEGF receptors (eg, ramucirumab), and their tyrosine kinase signaling (ie, tyrosine kinase inhibitors). The goal of the current review was to identify comparative preclinical data for the currently available VEGF-targeted therapies. Sources were compiled using PubMed searches (2007 to 2012), using search terms including, but not limited to: “bevacizumab,” “aflibercept,” “ramucirumab,” and “IMC-18F1.” Two preclinical studies were identified that compared bevacizumab and the newer agent, aflibercept. These studies identified some important differences in binding and pharmacodynamic activity, although the potential clinical relevance of these findings is not known. Newer antiangiogenesis therapies should help further expand treatment options for colorectal and other cancers. Comparative preclinical data on these agents is currently lacking.
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Petrelli F, Borgonovo K, Cabiddu M, Ghilardi M, Lonati V, Maspero F, Sauta MG, Beretta GD, Barni S. FOLFIRI-bevacizumab as first-line chemotherapy in 3500 patients with advanced colorectal cancer: a pooled analysis of 29 published trials. Clin Colorectal Cancer 2013; 12:145-51. [PMID: 23763824 DOI: 10.1016/j.clcc.2013.04.006] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2012] [Revised: 02/24/2013] [Accepted: 04/15/2013] [Indexed: 12/16/2022]
Abstract
Irinotecan and infusional bolus 5-fluorouracil (5-FU)-based chemotherapy (FOLFIRI [5-fluorouracil, folinic acid, irinotecan]) + bevacizumab (FOLFIRI-B) is 1 of the cornerstones of first-line treatment of advanced colorectal cancer (CRC). However, bevacizumab was approved for use after the AVF2107 trial that included a bolus 5-FU schedule (IFL [irinotecan + 5-FU + leucovorin]). No randomized trials have been published comparing FOLFIRI and FOLFIRI-B. The aim of this review is to pool all published data on the activity and efficacy of FOLFIRI-B as first-line therapy in treating advanced CRC in prospective and retrospective studies. We performed a systematic review, through PubMed and EMBASE, of all prospective and retrospective published studies exploring the efficacy of FOLFIRI-B as first-line chemotherapy in patients with advanced CRC. Pooled estimates of the response rate (RR) and weighted median of progression-free survival (PFS) and overall survival (OS) from all FOLFIRI-B-related studies were calculated. Rates of metastasectomy and bevacizumab-related severe toxicities were reported. A total of 29 studies (8 randomized controlled trials, 1 phase IV trial, 2 phase II trials, 4 observational studies, 4 prospective nonrandomized cohort studies, and 10 retrospective case series) were retrieved for a total of 3502 patients. Overall, the pooled RR (n = 22 publications) was 51.4%. Median PFS and OS (n = 25 and 20 publications) were 10.8 months (95% confidence interval [CI], 8.9-12.8) and 23.7 months (95% CI, 18.1-31.6), respectively. The pooled rate of surgical resection of metastases (any site of surgery: n = 7 publications) was 9.3% (range, 3.6%-24%), and rate of liver resections (liver surgery only: n = 7 publications) was 18% (range 8%-25%). Grade 3-4 bevacizumab-related toxicities were also comparable with larger phase III trials. FOLFIRI-B is used worldwide as upfront treatment for stage IV CRC. This indication is confirmed by robust data about RR, PFS, and survival obtained, which this pooled analysis of 29 trials also found. FOLFIRI-B remains 1 of the referent combinations when bevacizumab is considered as first-line therapy.
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Affiliation(s)
- Fausto Petrelli
- Medical Oncology Unit, Oncology Department, Azienda Ospedaliera Treviglio, Treviglio (BG), Italy.
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45
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Infante JR, Reid TR, Cohn AL, Edenfield WJ, Cescon TP, Hamm JT, Malik IA, Rado TA, McGee PJ, Richards DA, Tarazi J, Rosbrook B, Kim S, Cartwright TH. Axitinib and/or bevacizumab with modified FOLFOX-6 as first-line therapy for metastatic colorectal cancer: a randomized phase 2 study. Cancer 2013; 119:2555-63. [PMID: 23605883 DOI: 10.1002/cncr.28112] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2012] [Revised: 02/12/2013] [Accepted: 02/19/2013] [Indexed: 01/13/2023]
Abstract
BACKGROUND In this multicenter, open-label, randomized phase 2 trial, the authors evaluated the vascular endothelial growth factor receptor inhibitor axitinib, bevacizumab, or both in combination with chemotherapy as first-line treatment of metastatic colorectal cancer (mCRC). METHODS Patients with previously untreated mCRC were randomized 1:1:1 to receive continuous axitinib 5 mg twice daily, bevacizumab 5 mg/kg every 2 weeks, or axitinib 5 mg twice daily plus bevacizumab 2 mg/kg every 2 weeks, each in combination with modified 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX-6). The primary endpoint was the objective response rate (ORR). RESULTS In all, 126 patients were enrolled from August 2007 to September 2008. The ORR was numerically inferior in the axitinib arm (n = 42) versus the bevacizumab arm (n = 43; 28.6% vs 48.8%; 1-sided P = .97). Progression-free survival (PFS) (11.0 months vs 15.9 months; 1-sided P = .57) and overall survival (OS) (18.1 months vs 21.6 months; 1-sided P = .69) also were numerically inferior in the axitinib arm. Similarly, efficacy endpoints for the axitinib/bevacizumab arm (n = 41) were numerically inferior (ORR, 39%; PFS, 12.5 months; OS, 19.7 months). The patients who received axitinib had fewer treatment cycles compared with other arms. Common all-grade adverse events across all 3 treatment arms were fatigue, diarrhea, and nausea (all ≥49%). Hypertension and headache were more frequent in the patients who received axitinib. Patients in the bevacizumab arm had the longest treatment exposures and the highest rates of peripheral neuropathy. CONCLUSIONS Neither the addition of continuous axitinib nor the axitinib/bevacizumab combination to FOLFOX-6 improved ORR, PFS, or OS compared with bevacizumab as first-line treatment of mCRC.
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Affiliation(s)
- Jeffrey R Infante
- Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, Tennessee, USA.
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46
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Cartwright TH. Adverse events associated with antiangiogenic agents in combination with cytotoxic chemotherapy in metastatic colorectal cancer and their management. Clin Colorectal Cancer 2013; 12:86-94. [PMID: 23562587 DOI: 10.1016/j.clcc.2012.12.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2012] [Revised: 12/10/2012] [Accepted: 12/21/2012] [Indexed: 12/27/2022]
Abstract
Colorectal cancer (CRC) is the third most common cancer in men and women, and, despite advances in detection and treatment that result in a steadily decreasing incidence and mortality, remains a leading cause of death. The 5-year survival rate of persons with metastatic CRC (mCRC) is only 12%. With the recognition of vascularity as an important factor in tumor proliferation and growth, targeting angiogenesis pathways has been a major focus of research. The addition of bevacizumab, an inhibitor of the vascular endothelial growth factor (VEGF) pathway, to cytotoxic chemotherapy has improved response rates and survival of patients with mCRC. Aflibercept, a potent new multiple angiogenic factor trap that prevents not only VEGF-A but also VEGF-B and placental growth factor from activating their native receptors, has demonstrated efficacy in previously treated patients with mCRC. Phase I/II clinical trials and, more recently, a phase III clinical trial, have demonstrated effective antiangiogenic and cytotoxic activity with acceptable safety and tolerability. As is the case with bevacizumab, the optimal use of aflibercept requires appropriate management of the associated anti-VEGF adverse events and those associated with its use in combination with chemotherapy. These adverse events have previously been observed and are generally manageable with appropriate therapeutic intervention.
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47
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Leung HWC, Chan ALF, Leung MSH, Lu CL. Systematic review and quality assessment of cost-effectiveness analysis of pharmaceutical therapies for advanced colorectal cancer. Ann Pharmacother 2013; 47:506-18. [PMID: 23548649 DOI: 10.1345/aph.1r152] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
OBJECTIVE To systematically review and assess the quality of cost-effectiveness analyses (CEAs) of pharmaceutical therapies for metastatic colorectal cancer (mCRC). DATA SOURCES The MEDLINE, EMBASE, Cochrane, and EconLit databases were searched for the Medical Subject Headings or text key words quality-adjusted, QALY, life-year gained (LYG), and cost-effectiveness (January 1, 1999-December 31, 2009). STUDY SELECTION Original CEAs of mCRC pharmacotherapy published in English were included. CEAs that measured health effects in units other than quality-adjusted life years or LYG and letters to the editor, case reports, posters, and editorials were excluded. DATA EXTRACTION Each article was independently assessed by 2 trained reviewers according to a quality checklist created by the Panel on Cost-Effectiveness in Health and Medicine. RESULTS Twenty-four CEA studies pertaining to pharmaceutical therapies for mCRC were identified. All studies showed a wide variation in methodologic approaches, which resulted in a different range of incremental cost-effectiveness ratios reported for each regimen. We found common methodologic flaws in a significant number of CEA studies, including lack of clear description for critique of data quality; lack of method for adjusting costs for inflation and methods for obtaining expert judgment; no results of model validation; wide differences in the types of perspective, time horizon, study design, cost categories, and effect outcomes; and no quality assessment of data (cost and effectiveness) for the interventions evaluation. CONCLUSIONS This study has shown a wide variation in the methodology and quality of cost-effectiveness analysis for mCRC. Improving quality and harmonization of CEA for cancer treatment is needed. Further study is suggested to assess the quality of CEA methodology outside the mCRC disease state.
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Affiliation(s)
- Henry W C Leung
- Department of Radiation Therapy, Min-Sheng General Hospital, Taiwan
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48
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Dietvorst MHP, Eskens FALM. Current and Novel Treatment Options for Metastatic Colorectal Cancer: Emphasis on Aflibercept. BIOLOGICS IN THERAPY 2013; 3:25-33. [PMID: 24392302 PMCID: PMC3873022 DOI: 10.1007/s13554-013-0009-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/14/2013] [Indexed: 11/28/2022]
Abstract
Worldwide, colorectal cancer (CRC) is the third most frequently diagnosed cancer in men and the second in women. Metastatic disease develops in more than half of the patients and carries a poor prognosis. Over the past three decades, significant advances have been made in the treatment of metastatic colorectal cancer (mCRC). The development of new cytotoxic agents and the incorporation of target-specific agents in first-, second-, third-, and nowadays even fourth-line treatment has prolonged median overall survival up to 24–28 months. However, 5-year survival rates remain disappointingly low. This review summarizes the currently available cytotoxic treatment options for mCRC, and highlights the further emerging role of vascular endothelial growth factor (VEGF)-inhibiting strategies, emphasizing the role of aflibercept. Aflibercept is a recombinant fusion protein with high VEGF affinity, and is the second antiangiogenic agent to obtain registration in the treatment of mCRC.
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Affiliation(s)
- Maria H P Dietvorst
- Department of Medical Oncology, Erasmus University Medical Center, Daniel den Hoed Cancer Center, Room HE120, PO BOX 2040, 3000 CA Rotterdam, The Netherlands
| | - Ferry A L M Eskens
- Department of Medical Oncology, Erasmus University Medical Center, Daniel den Hoed Cancer Center, Room HE120, PO BOX 2040, 3000 CA Rotterdam, The Netherlands
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Rossi L, Veltri E, Zullo A, Zoratto F, Colonna M, Di Seri M, Longo F, Mottolese M, Giannarelli D, Ruco L, Romiti A, Barucca V, Adua D, Tomao S. Bevacizumab plus chemotherapy in metastatic colorectal cancer patients treated in clinical practice. Future Oncol 2013; 8:1193-7. [PMID: 23030493 DOI: 10.2217/fon.12.108] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
AIM The effect of KRAS status on response to bevacizumab plus chemotherapy in metastatic colorectal cancer is still unclear. We aimed to evaluate the overall clinical response to such a therapy in clinical practice and assess the role of KRAS status on therapy response. PATIENTS & METHODS This was a retrospective study enrolling 108 metastatic colorectal cancer patients. KRAS mutation analysis was performed by PCR. RESULTS Overall, 41.7% of patients had stable disease, 39.8% a partial response, 3.7% a complete response and 14.8% disease progression. Both clinical benefit and objective response rate tended to be higher in patients with only hepatic metastases than those with extrahepatic or multiple metastases. Response to therapy would appear to be independent of KRAS status, but larger studies are needed. CONCLUSION Bevacizumab plus chemotherapy provides clinical benefit and objective response rate in patients with metastatic colorectal cancer independently of KRAS expression, especially in those patients with only liver metastases.
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Affiliation(s)
- Luigi Rossi
- Oncology, S. M. Goretti Hospital, Latina, Sapienza University, Rome, Italy.
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50
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Guan ZZ, Xu JM, Luo RC, Feng FY, Wang LW, Shen L, Yu SY, Ba Y, Liang J, Wang D, Qin SK, Wang JJ, He J, Qi C, Xu RH. Efficacy and safety of bevacizumab plus chemotherapy in Chinese patients with metastatic colorectal cancer: a randomized phase III ARTIST trial. CHINESE JOURNAL OF CANCER 2013; 30:682-9. [PMID: 21959045 PMCID: PMC4012268 DOI: 10.5732/cjc.011.10188] [Citation(s) in RCA: 91] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The efficacy and safety of bevacizumab with modified irinotecan, leucovorin bolus, and 5-fluorouracil intravenous infusion (mIFL) in the first-line treatment of metastatic colorectal cancer (mCRC) has not been well evaluated in randomized clinical trials in Chinese patients. We conducted a phrase III trial in which patients with previously untreated mCRC were randomized 2:1 to the mIFL [irinotecan (125 mg/m2), leucovorin (20 mg/m2) bolus, and 5-fluorouracil intravenous infusion (500 mg/m2) weekly for four weeks every six weeks] plus bevacizumab (5 mg/kg every two weeks) group and the mIFL group, respectively. Co-primary objectives were progression-free survival (PFS) and 6-month PFS rate. In total, 214 patients were enrolled. Our results showed that addition of bevacizumab to mIFL significantly improved median PFS (4.2 months in the mIFL group vs. 8.3 months in the bevacizumab plus mIFL group, P < 0.001), 6-month PFS rate (25.0% vs. 62.6%, P < 0.001), median overall survival (13.4 months vs. 18.7 months, P = 0.014), and response rate (17% vs. 35%, P = 0.013). Grades 3 and 4 adverse events included diarrhea (21% in the mIFL group and 26% in the bevacizumab plus mIFL group) and neutropenia (19% in the mIFL group and 33% in the bevacizumab plus mIFL group). No wound-healing complications or congestive heart failure occurred. Our results suggested that bevacizumab plus mIFL is effective and well tolerated as first-line treatment for Chinese patients with mCRC. Clinical benefit and safety profiles were consistent with those observed in pivotal phase III trials with mainly Caucasian patients.
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Affiliation(s)
- Zhong-Zhen Guan
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.
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