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Chen EX, Kavan P, Tehfe M, Kortmansky JS, Sawyer MB, Chiorean EG, Lieu CH, Polite B, Wong L, Fakih M, Spencer K, Chaves J, Li C, Leconte P, Adelberg D, Kim R. Pembrolizumab Plus Binimetinib With or Without Chemotherapy for MSS/pMMR Metastatic Colorectal Cancer: Outcomes From KEYNOTE-651 Cohorts A, C, and E. Clin Colorectal Cancer 2024; 23:183-193. [PMID: 38653648 DOI: 10.1016/j.clcc.2024.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 03/15/2024] [Accepted: 03/28/2024] [Indexed: 04/25/2024]
Abstract
BACKGROUND Cohorts A, C, and E of the phase Ib KEYNOTE-651 study evaluated pembrolizumab + binimetinib ± chemotherapy in microsatellite stable/mismatch repair-proficient metastatic colorectal cancer. PATIENTS AND METHODS Patients received pembrolizumab 200 mg every 3 weeks plus binimetinib 30 mg twice daily alone (cohort A; previously treated with any chemotherapy) or with 5-fluorouracil, leucovorin, oxaliplatin (cohort C; previously untreated) or 5-fluorouracil, leucovorin, irinotecan (cohort E; previously treated with 1 line of therapy including fluoropyrimidine + oxaliplatin-based regimen) every 2 weeks. Binimetinib dose-escalation to 45 mg twice daily was planned in all cohorts using a modified toxicity probability interval design (target dose-limiting toxicity [DLT], 30%). The primary endpoint was safety; investigator-assessed objective response rate was secondary. RESULTS In cohort A, 1/6 patients (17%) had DLTs with binimetinib 30 mg; none occurred in 14 patients with 45 mg. In cohort C, 3/9 patients (33%) had DLTs with binimetinib 30 mg; dose was not escalated to 45 mg. In cohort E, 1/5 patients (20%) had DLTs with binimetinib 30 mg; 5/10 patients (50%) had DLTs with 45 mg. Enrollment was stopped in cohort E binimetinib 45 mg and deescalated to 30 mg; 2/4 additional patients (50%) had DLTs with binimetinib 30 mg (total 3/9 [33%] had DLTs with binimetinib 30 mg). Objective response rate was 0% in cohort A, 9% in cohort C, and 15% in cohort E. CONCLUSION Per DLT criteria, binimetinib + pembrolizumab (cohort A) was tolerable, binimetinib + pembrolizumab + 5-fluorouracil, leucovorin, oxaliplatin (cohort C) did not qualify for binimetinib dose escalation to 45 mg, and binimetinib + pembrolizumab + 5-fluorouracil, leucovorin, irinotecan (cohort E) required binimetinib dose reduction from 45 to 30 mg. No new safety findings were observed across cohorts. There was no apparent additive efficacy when binimetinib + pembrolizumab was added to chemotherapy. Data did not support continued enrollment in cohorts C and E.
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Affiliation(s)
- Eric X Chen
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, ON M5G 2C1, Canada.
| | - Petr Kavan
- Department of Medicine and Oncology, Sir Mortimer B. Davis Jewish General Hospital, Segal Cancer Centre, McGill University, Montreal, QC H3T 1E2, Canada
| | - Mustapha Tehfe
- Hematology and Medical Oncology Division, Centre Hospitalier Universitaire de Montreal, University of Montreal, Montreal, QC H2X 0C1, Canada
| | | | - Michael B Sawyer
- Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB T6G 1Z2, Canada
| | - E Gabriela Chiorean
- Division of Medical Oncology, Department of Medicine, University of Washington and Fred Hutchinson Cancer Center, Clinical Research Division, Seattle, WA
| | - Christopher H Lieu
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO
| | - Blase Polite
- Department of Hematology and Oncology, University of Chicago, Chicago, IL
| | - Lucas Wong
- Division of Hematology and Oncology, Baylor Scott and White, Temple, TX
| | - Marwan Fakih
- Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA
| | - Kristen Spencer
- Department of Medicine, Perlmutter Cancer Center of NYU Langone Health and Department of Internal Medicine NYU Grossman School of Medicine, New York, NY
| | - Jorge Chaves
- Medical Oncology, Northwest Medical Specialties, PLLC, Tacoma, WA
| | | | | | | | - Richard Kim
- Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, FL
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Kim R, Tehfe M, Kavan P, Chaves J, Kortmansky JS, Chen EX, Lieu CH, Wong L, Fakih M, Spencer K, Zhao Q, Predoiu R, Li C, Leconte P, Adelberg D, Chiorean EG. Pembrolizumab Plus mFOLFOX7 or FOLFIRI for Microsatellite Stable/Mismatch Repair-Proficient Metastatic Colorectal Cancer: KEYNOTE-651 Cohorts B and D. Clin Colorectal Cancer 2024; 23:118-127.e6. [PMID: 38762348 DOI: 10.1016/j.clcc.2024.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 03/15/2024] [Accepted: 03/28/2024] [Indexed: 05/20/2024]
Abstract
BACKGROUND The phase 1b KEYNOTE-651 study evaluated pembrolizumab plus chemotherapy in microsatellite stable or mismatch repair-proficient metastatic colorectal cancer. PATIENTS AND METHODS Patients with microsatellite stable or mismatch repair-proficient metastatic colorectal cancer received pembrolizumab 200 mg every 3 weeks plus 5-fluorouracil, leucovorin, oxaliplatin (previously untreated; cohort B) or 5-fluorouracil, leucovorin, irinotecan (previously treated with fluoropyrimidine plus oxaliplatin; cohort D) every 2 weeks. Primary end point was safety; investigator-assessed objective response rate per RECIST v1.1 was secondary and biomarker analysis was exploratory. RESULTS Thirty-one patients were enrolled in cohort B and 32 in cohort D; median follow-up was 30.2 and 33.5 months, respectively. One dose-limiting toxicity (grade 3 small intestine obstruction) occurred in cohort D. In cohort B, grade 3 or 4 treatment-related adverse events (AEs) occurred in 18 patients (58%), most commonly neutropenia and decreased neutrophil count (n = 5 each). In cohort D, grade 3 or 4 treatment-related AEs occurred in 17 patients (53%), most commonly neutropenia (n = 7). No grade 5 treatment-related AEs occurred. Objective response rate was 61% in cohort B (KRAS wildtype: 71%; KRAS mutant: 53%) and 25% in cohort D (KRAS wildtype: 47%; KRAS mutant: 6%). In both cohorts, PD-L1 combined positive score and T-cell-inflamed gene expression profiles were higher and HER2 expression was lower in responders than nonresponders. No association between tumor mutational burden and response was observed. CONCLUSION Pembrolizumab plus 5-fluorouracil, leucovorin, oxaliplatin/5-fluorouracil, leucovorin, irinotecan demonstrated an acceptable AE profile. Efficacy data appeared comparable with current standard of care (including by KRAS mutation status). Biomarker analyses were hypothesis-generating, warranting further exploration. CLINICALTRIALS GOV IDENTIFIER ClinicalTrials.gov; NCT03374254.
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Affiliation(s)
- Richard Kim
- Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, FL.
| | - Mustapha Tehfe
- Hematology and Medical Oncology Division, Centre Hospitalier de l'Université de Montréal, Montréal, Canada
| | - Petr Kavan
- Department of Medicine and Oncology, Sir Mortimer B. Davis Jewish General Hospital, Segal Cancer Centre, McGill University, Montreal, Canada
| | - Jorge Chaves
- Medical Oncology, Northwest Medical Specialties, Tacoma, WA
| | | | - Eric X Chen
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Canada
| | - Christopher H Lieu
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO
| | - Lucas Wong
- Division of Hematology and Oncology, Baylor Scott and White, Temple, TX
| | - Marwan Fakih
- Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA
| | - Kristen Spencer
- Department of Medicine, Perlmutter Cancer Center of NYU Langone Health and Department of Internal Medicine NYU Grossman School of Medicine, New York, NY
| | - Qing Zhao
- Department of Medical Oncology, BARDS, Merck & Co., Inc., Rahway, NJ
| | - Raluca Predoiu
- Department of Medical Oncology, BARDS, Merck & Co., Inc., Rahway, NJ
| | - Chenxiang Li
- Department of Medical Oncology, BARDS, Merck & Co., Inc., Rahway, NJ
| | - Pierre Leconte
- Department of Medical Oncology, MSD France, Puteaux, France
| | - David Adelberg
- Department of Medical Oncology, Merck & Co., Inc., Rahway, NJ
| | - E Gabriela Chiorean
- Division of Medical Oncology, Department of Medicine, University of Washington and Fred Hutchinson Cancer Center, Clinical Research Division, Seattle, WA
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Liao PF, Wu TW, Peng TR. Monoclonal Antibodies for First-Line Treatment of Metastatic Colorectal Cancer. Am J Ther 2024; 31:e286-e297. [PMID: 35972911 DOI: 10.1097/mjt.0000000000001547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND In addition to discontinuing treatment at disease progression, cumulative toxicity limitations and genetic mutations play important roles in chemotherapy choice in metastatic colorectal cancer (mCRC). However, in recent years, targeted therapies, such as immune checkpoint inhibitors or monoclonal antibodies (MoAbs), have been used with chemotherapy to improve clinical outcomes in patients with mCRC. AREAS OF UNCERTAINTY Approximately 15% of patients with CRC would be eligible for further targeted therapy with immune checkpoint inhibitors based on genetic testing, but most patients with CRC would not qualify, especially Kirsten rat sarcoma wild-type. Therefore, adding MoAb is only an option for most patients until disease progression or unacceptable toxicity occurs. However, the results are not consistent with the combination of MoAb and different chemotherapy bases. In addition, most results from combining MoAb with different chemotherapy bases are not consistent. DATA SOURCES This meta-analysis includes published of the PubMed and Embase databases, limited to English literature, and patients were treated with MoAb combination. Randomized control trials conducted published up to May 2021 were considered for inclusion. THERAPEUTIC ADVANCES Fluoropyrimidine-based chemotherapy has been the backbone of palliative therapy for mCRC, with demonstrated benefits. This article will review the efficacy and safety of randomized control trials comparing different MoAb with fluoropyrimidine-based chemotherapy as first-line therapy for patients with mCRC, particularly in Kirsten rat sarcoma wild-type. CONCLUSION This meta-analysis revealed that MoAb plus chemotherapy has better progression-free survival and objective response rate than chemotherapy alone. However, treatment-related serious adverse events (grade ≥ 3) should be considered, particularly severe rash, diarrhea, and hypertension.
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Affiliation(s)
- Pei-Fei Liao
- Department of Pharmacy, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan, Republic of China
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Perioperative second-line chemotherapy is beneficial for resectable liver metastases that occur during or early after adjuvant chemotherapy for colorectal cancer. Int J Colorectal Dis 2022; 37:805-814. [PMID: 35188594 DOI: 10.1007/s00384-022-04111-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/07/2022] [Indexed: 02/04/2023]
Abstract
BACKGROUND The prognosis of patients with liver metastases during or early after adjuvant chemotherapy for colorectal cancer (CRC) is significantly worse. This study aimed to explore the efficacy of perioperative second-line chemotherapy in prolonging survival in those patients. METHODS Patients who underwent liver resection, with resectable liver metastases that occurred within 12 months after the last cycle of adjuvant chemotherapy for CRC, from January 2006 to December 2019, were included. The long-term outcome of overall survival (OS) and progression-free survival (PFS) between different groups was analyzed. RESULTS A total of 200 patients were included, of whom 112 underwent direct hepatectomy and 88 received upfront second-line chemotherapy. OS and PFS were significantly better in patients receiving upfront second-line chemotherapy than direct surgery (PFS, P = 0.016; OS, P = 0.013). Further analysis showed that perioperative second-line chemotherapy could provide a greater survival benefit, which was also confirmed by propensity score matching (OS: P = 0.03; PFS: P = 0.04). Multivariate analysis determined that perioperative second-line chemotherapy was an independent factor influencing OS (OR [95% CI]: 0.468 [0.294-0.744], P = 0.001) and PFS (OR [95% CI]: 0.517 [0.353-0.758], P = 0.001). DISCUSSION Perioperative second-line chemotherapy could improve the survival of patients who underwent hepatectomy, with resectable liver metastases that occurred during or early after adjuvant chemotherapy for CRC.
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Synergistic combination of PMBA and 5-Fluorouracil (5-FU) in targeting mutant KRAS in 2D and 3D colorectal cancer cells. Heliyon 2022; 8:e09103. [PMID: 35445157 PMCID: PMC9014391 DOI: 10.1016/j.heliyon.2022.e09103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 11/12/2021] [Accepted: 03/09/2022] [Indexed: 11/20/2022] Open
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Fukui T, Suzuki K, Ichida K, Takayama Y, Kakizawa N, Muto Y, Hasegawa F, Watanabe F, Kikugawa R, Saito M, Tsujinaka S, Miyakura Y, Rikiyama T. Sequential administration of XELOX and XELIRI is effective, feasible and well tolerated by patients with metastatic colorectal cancer. Oncol Lett 2017; 13:4947-4952. [PMID: 28599498 PMCID: PMC5452954 DOI: 10.3892/ol.2017.6100] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Accepted: 03/03/2017] [Indexed: 02/01/2023] Open
Abstract
Sequential administration of the chemotherapy regimes capecitabine and oxaliplatin (XELOX) and capecitabine and irinotecan (XELIRI) in the first- to second-line treatment setting would allow patients to be managed more easily in an outpatient unit. However, a small number of studies have raised concerns of cumulative adverse events as a consequence of the continuous use of capecitabine. To investigate this, the present study conducted a retrospective review of 81 consecutive metastatic colorectal cancer (mCRC) patients treated with the oxaliplatin, fluorouracil and leucovorin-irinotecan, fluorouracil and leucovorin (FOLFOX-FOFIRI/F-F) regimen (n=40) or the XELOX-XELIRI (X-X) regimen (n=41) in first- to second-line chemotherapy in Saitama Medical Center between 2006 and 2012. The disease control rate (DCR), the progression free survival (PFS), the overall survival (OS) and the time to failure of strategy (TFS) from first to second-line chemotherapy, as well as adverse events, were assessed and compared between patients receiving X-X or F-F. A total of 10 and 20 patients were additionally treated with bevacizumab in the F-F and X-X regimens, respectively, during first or second-line chemotherapy. There was no significant difference in DCR and the median PFS between the two regimens for first or second-line chemotherapy. There was no significant difference in the median OS and TFS between the two regimens (OS=24.5 and TFS=14 months in the F-F vs. 23.2 and 12.0 months in the X-X). Regarding adverse events, 45.0% of patients (18/40) exhibited grade 3-4 neutropenia throughout treatment with F-F. Whilst, 15.0% of patients (6/41) exhibited grade 3 hypertension throughout treatment with X-X, which was effectively controlled by a single antihypertensive drug. The results show that sequential administration of X-X is as effective and feasible as F-F treatment, while additionally reducing the frequency of infusion visits and eliminating the need for a central venous access device or home infusion pump, thereby offering a more convenient treatment option to patients with mCRC.
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Affiliation(s)
- Taro Fukui
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Saitama 330-8503, Japan
| | - Koichi Suzuki
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Saitama 330-8503, Japan
| | - Kosuke Ichida
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Saitama 330-8503, Japan
| | - Yuji Takayama
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Saitama 330-8503, Japan
| | - Nao Kakizawa
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Saitama 330-8503, Japan
| | - Yuta Muto
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Saitama 330-8503, Japan
| | - Fumi Hasegawa
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Saitama 330-8503, Japan
| | - Fumiaki Watanabe
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Saitama 330-8503, Japan
| | - Rina Kikugawa
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Saitama 330-8503, Japan
| | - Masaaki Saito
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Saitama 330-8503, Japan
| | - Shingo Tsujinaka
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Saitama 330-8503, Japan
| | - Yasuyuki Miyakura
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Saitama 330-8503, Japan
| | - Toshiki Rikiyama
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Saitama 330-8503, Japan
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Mocellin S, Baretta Z, Roqué i Figuls M, Solà I, Martin‐Richard M, Hallum S, Bonfill Cosp X, Cochrane Colorectal Cancer Group. Second-line systemic therapy for metastatic colorectal cancer. Cochrane Database Syst Rev 2017; 1:CD006875. [PMID: 28128439 PMCID: PMC6464923 DOI: 10.1002/14651858.cd006875.pub3] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND The therapeutic management of people with metastatic colorectal cancer (CRC) who did not respond to first-line treatment represents a formidable challenge. OBJECTIVES To determine the efficacy and toxicity of second-line systemic therapy in people with metastatic CRC. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2016, Issue 4), Ovid MEDLINE (1950 to May 2016), Ovid MEDLINE In-process & Other Non-Indexed Citations (1946 to May 2016) and Ovid Embase (1974 to May 2016). There were no language or date of publication restrictions. SELECTION CRITERIA Randomized controlled trials (RCTs) assessing the efficacy (survival, tumour response) and toxicity (incidence of severe adverse effects (SAEs)) of second-line systemic therapy (single or combined treatment with any anticancer drug, at any dose and number of cycles) in people with metastatic CRC that progressed, recurred or did not respond to first-line systemic therapy. DATA COLLECTION AND ANALYSIS Authors performed a descriptive analysis of each included RCT in terms of primary (survival) and secondary (tumour response, toxicity) endpoints. In the light of the variety of drug regimens tested in the included trials, we could carry out meta-analysis considering classes of (rather than single) anticancer regimens; to this aim, we applied the random-effects model to pool the data. We used hazard ratios (HRs) and risk ratios (RRs) to describe the strength of the association for survival (overall (OS) and progression-free survival (PFS)) and dichotomous (overall response rate (ORR) and SAE rate) data, respectively, with 95% confidence intervals (CI). MAIN RESULTS Thirty-four RCTs (enrolling 13,787 participants) fulfilled the eligibility criteria. Available evidence enabled us to address multiple clinical issues regarding the survival effects of second-line systemic therapy of people with metastatic CRC.1. Chemotherapy (irinotecan) was more effective than best supportive care (HR for OS: 0.58, 95% CI 0.43 to 0.80; 1 RCT; moderate-quality evidence); 2. modern chemotherapy (FOLFOX (5-fluorouracil plus leucovorin plus oxaliplatin), irinotecan) is more effective than outdated chemotherapy (5-fluorouracil) (HR for PFS: 0.59, 95% CI 0.49 to 0.73; 2 RCTs; high-quality evidence) (HR for OS: 0.69, 95% CI 0.51 to 0.94; 1 RCT; moderate-quality evidence); 3. irinotecan-based combinations were more effective than irinotecan alone (HR for PFS: 0.68, 95% CI 0.60 to 0.76; 6 RCTs; moderate-quality evidence); 4. targeted agents improved the efficacy of conventional chemotherapy both when considered together (HR for OS: 0.84, 95% CI 0.77 to 0.91; 6 RCTs; high-quality evidence) and when bevacizumab was used alone (HR for PFS: 0.67, 95% CI 0.60 to 0.75; 4 RCTs; high-quality evidence).With regard to secondary endpoints, tumour response rates generally paralleled the survival results; moreover, higher anticancer efficacy was generally associated with worse treatment-related toxicity, with the important exception of bevacizumab-containing regimens, where the addition of the targeted agent to chemotherapy did not result in a significant increase in the rate of SAE. Finally, we found that oral (instead of intravenous) fluoropyrimidines significantly reduced the incidence of adverse effects (without compromising efficacy) in people treated with oxaliplatin-based regimens.We could not draw any conclusions on other debated aspects in this field of oncology, such as ranking of treatments (not all possible comparisons have been tested and many comparisons were based on single trials enrolling a small number of participants) and quality of life (virtually no data available). AUTHORS' CONCLUSIONS Systemic therapy offers a survival benefit to people with metastatic CRC who did not respond to first-line treatment, especially when targeted agents are combined with conventional chemotherapeutic drugs. Further research is needed to define the optimal regimen and to identify people who most benefit from each treatment.
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Affiliation(s)
- Simone Mocellin
- University of PadovaDepartment of Surgery, Oncology and GastroenterologyVia Giustiniani 2PadovaVenetoItaly35128
- IOV‐IRCCSIstituto Oncologico VenetoPadovaItaly35100
| | - Zora Baretta
- Ospedale di MontecchioU.O.C. di Oncologia ULSS5 Ovest VicentinoMontecchio MaggioreVicenzaItaly
| | - Marta Roqué i Figuls
- CIBER Epidemiología y Salud Pública (CIBERESP)Iberoamerican Cochrane Centre ‐ Biomedical Research Institute Sant Pau (IIB Sant Pau)Sant Antoni Maria Claret 171Edifici Casa de ConvalescènciaBarcelonaCatalunyaSpain08041
| | - Ivan Solà
- CIBER Epidemiología y Salud Pública (CIBERESP) ‐ Universitat Autònoma de BarcelonaIberoamerican Cochrane Centre ‐ Biomedical Research Institute Sant Pau (IIB Sant Pau)Sant Antoni Maria Claret 167Pavilion 18BarcelonaCatalunyaSpain08025
| | - Marta Martin‐Richard
- Hospital de la Santa Creu i Sant PauClinical OncologySant Antoni Maria Claret 167BarcelonaSpain08025
| | - Sara Hallum
- CochraneCochrane Colorectal Cancer Group23 Bispebjerg BakkeCopenhagenDenmarkDK 2400 NV
| | - Xavier Bonfill Cosp
- CIBER Epidemiología y Salud Pública (CIBERESP)Iberoamerican Cochrane Centre ‐ Biomedical Research Institute Sant Pau (IIB Sant Pau)Sant Antoni Maria Claret 171Edifici Casa de ConvalescènciaBarcelonaCatalunyaSpain08041
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Use of Bevacizumab in the Management of Potentially Resectable Colorectal Liver Metastases: Safety, Pathologic Assessment and Benefit. CURRENT COLORECTAL CANCER REPORTS 2016. [DOI: 10.1007/s11888-016-0326-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Van Cutsem E, Cervantes A, Adam R, Sobrero A, Van Krieken JH, Aderka D, Aranda Aguilar E, Bardelli A, Benson A, Bodoky G, Ciardiello F, D'Hoore A, Diaz-Rubio E, Douillard JY, Ducreux M, Falcone A, Grothey A, Gruenberger T, Haustermans K, Heinemann V, Hoff P, Köhne CH, Labianca R, Laurent-Puig P, Ma B, Maughan T, Muro K, Normanno N, Österlund P, Oyen WJG, Papamichael D, Pentheroudakis G, Pfeiffer P, Price TJ, Punt C, Ricke J, Roth A, Salazar R, Scheithauer W, Schmoll HJ, Tabernero J, Taïeb J, Tejpar S, Wasan H, Yoshino T, Zaanan A, Arnold D. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol 2016; 27:1386-422. [PMID: 27380959 DOI: 10.1093/annonc/mdw235] [Citation(s) in RCA: 2402] [Impact Index Per Article: 266.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Accepted: 05/31/2016] [Indexed: 02/11/2024] Open
Abstract
Colorectal cancer (CRC) is one of the most common malignancies in Western countries. Over the last 20 years, and the last decade in particular, the clinical outcome for patients with metastatic CRC (mCRC) has improved greatly due not only to an increase in the number of patients being referred for and undergoing surgical resection of their localised metastatic disease but also to a more strategic approach to the delivery of systemic therapy and an expansion in the use of ablative techniques. This reflects the increase in the number of patients that are being managed within a multidisciplinary team environment and specialist cancer centres, and the emergence over the same time period not only of improved imaging techniques but also prognostic and predictive molecular markers. Treatment decisions for patients with mCRC must be evidence-based. Thus, these ESMO consensus guidelines have been developed based on the current available evidence to provide a series of evidence-based recommendations to assist in the treatment and management of patients with mCRC in this rapidly evolving treatment setting.
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Affiliation(s)
- E Van Cutsem
- Digestive Oncology, University Hospitals Gasthuisberg Leuven and KU Leuven, Leuven, Belgium
| | - A Cervantes
- Medical Oncology Department, INCLIVA University of Valencia, Valencia, Spain
| | - R Adam
- Hepato-Biliary Centre, Paul Brousse Hospital, Villejuif, France
| | - A Sobrero
- Medical Oncology, IRCCS San Martino Hospital, Genova, Italy
| | - J H Van Krieken
- Research Institute for Oncology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
| | - D Aderka
- Division of Oncology, Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel
| | - E Aranda Aguilar
- Medical Oncology Department, University Hospital Reina Sofia, Cordoba, Spain
| | - A Bardelli
- School of Medicine, University of Turin, Turin, Italy
| | - A Benson
- Division of Hematology/Oncology, Northwestern Medical Group, Chicago, USA
| | - G Bodoky
- Department of Oncology, St László Hospital, Budapest, Hungary
| | - F Ciardiello
- Division of Medical Oncology, Seconda Università di Napoli, Naples, Italy
| | - A D'Hoore
- Abdominal Surgery, University Hospitals Gasthuisberg Leuven and KU Leuven, Leuven, Belgium
| | - E Diaz-Rubio
- Medical Oncology Department, Hospital Clínico San Carlos, Madrid, Spain
| | - J-Y Douillard
- Medical Oncology, Institut de Cancérologie de l'Ouest (ICO), St Herblain
| | - M Ducreux
- Department of Medical Oncology, Gustave Roussy, Université Paris-Saclay, Villejuif, France
| | - A Falcone
- Department of Medical Oncology, University of Pisa, Pisa, Italy Division of Medical Oncology, Department of Oncology, University Hospital 'S. Chiara', Istituto Toscano Tumori, Pisa, Italy
| | - A Grothey
- Division of Medical Oncology, Mayo Clinic, Rochester, USA
| | - T Gruenberger
- Department of Surgery I, Rudolfstiftung Hospital, Vienna, Austria
| | - K Haustermans
- Department of Radiation Oncology, University Hospitals Gasthuisberg and KU Leuven, Leuven, Belgium
| | - V Heinemann
- Comprehensive Cancer Center, University Clinic Munich, Munich, Germany
| | - P Hoff
- Instituto do Câncer do Estado de São Paulo, University of São Paulo, São Paulo, Brazil
| | - C-H Köhne
- Northwest German Cancer Center, University Campus Klinikum Oldenburg, Oldenburg, Germany
| | - R Labianca
- Cancer Center, Ospedale Giovanni XXIII, Bergamo, Italy
| | - P Laurent-Puig
- Digestive Oncology Department, European Hospital Georges Pompidou, Paris, France
| | - B Ma
- Department of Clinical Oncology, Prince of Wales Hospital, State Key Laboratory in Oncology in South China, Chinese University of Hong Kong, Shatin, Hong Kong
| | - T Maughan
- CRUK/MRC Oxford Institute for Radiation Oncology, Gray Laboratories, University of Oxford, Oxford, UK
| | - K Muro
- Department of Clinical Oncology and Outpatient Treatment Center, Aichi Cancer Center Hospital, Nagoya, Japan
| | - N Normanno
- Cell Biology and Biotherapy Unit, I.N.T. Fondazione G. Pascale, Napoli, Italy
| | - P Österlund
- Helsinki University Central Hospital, Comprehensive Cancer Center, Helsinki, Finland Department of Oncology, University of Helsinki, Helsinki, Finland
| | - W J G Oyen
- The Institute of Cancer Research and The Royal Marsden Hospital, London, UK
| | - D Papamichael
- Department of Medical Oncology, Bank of Cyprus Oncology Centre, Nicosia, Cyprus
| | - G Pentheroudakis
- Department of Medical Oncology, University of Ioannina, Ioannina, Greece
| | - P Pfeiffer
- Department of Oncology, Odense University Hospital, Odense, Denmark
| | - T J Price
- Haematology and Medical Oncology Unit, Queen Elizabeth Hospital, Woodville, Australia
| | - C Punt
- Department of Medical Oncology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
| | - J Ricke
- Department of Radiology and Nuclear Medicine, University Clinic Magdeburg, Magdeburg, Germany
| | - A Roth
- Digestive Tumors Unit, Geneva University Hospitals (HUG), Geneva, Switzerland
| | - R Salazar
- Catalan Institute of Oncology (ICO), Barcelona, Spain
| | - W Scheithauer
- Department of Internal Medicine I and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - H J Schmoll
- Department of Internal Medicine IV, University Clinic Halle, Martin-Luther-University Halle-Wittenberg, Halle, Germany
| | - J Tabernero
- Medical Oncology Department, Vall d' Hebron University Hospital, Vall d'Hebron Institute of Oncology (V.H.I.O.), Barcelona, Spain
| | - J Taïeb
- Digestive Oncology Department, European Hospital Georges Pompidou, Paris, France
| | - S Tejpar
- Digestive Oncology, University Hospitals Gasthuisberg Leuven and KU Leuven, Leuven, Belgium
| | - H Wasan
- Department of Cancer Medicine, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK
| | - T Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan
| | - A Zaanan
- Digestive Oncology Department, European Hospital Georges Pompidou, Paris, France
| | - D Arnold
- Instituto CUF de Oncologia (ICO), Lisbon, Portugal
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10
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Thromboembolic Disease in Advanced Colorectal Cancer Treated with Chemotherapy and Bevacizumab: A Case of Real “Pan-Thrombosis”. TUMORI JOURNAL 2015; 101:e32-3. [DOI: 10.5301/tj.5000258] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/31/2014] [Indexed: 12/21/2022]
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11
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Salah S, Ardissone F, Gonzalez M, Gervaz P, Riquet M, Watanabe K, Zabaleta J, Al-Rimawi D, Toubasi S, Massad E, Lisi E, Hamed OH. Pulmonary metastasectomy in colorectal cancer patients with previously resected liver metastasis: pooled analysis. Ann Surg Oncol 2014; 22:1844-50. [PMID: 25326396 DOI: 10.1245/s10434-014-4173-9] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2014] [Indexed: 12/15/2022]
Abstract
BACKGROUND Data addressing the outcomes and patterns of recurrence after pulmonary metastasectomy (PM) in patients with colorectal cancer (CRC) and previously resected liver metastasis are limited. METHODS We searched the PubMed database for studies assessing PM in CRC and gathered individual data for patients who had PM and a previous curative liver resection. The influence of potential factors on overall survival (OS) was analyzed through univariate and multivariate analysis. RESULTS Between 1983 and 2009, 146 patients from five studies underwent PM and had previous liver resection. The median interval from resection of liver metastasis until detection of lung metastasis and the median follow-up from PM were 23 and 48 months, respectively. Five-year OS and recurrence-free survival rates calculated from the date of PM were 54.4 and 29.3 %, respectively. Factors predicting inferior OS in univariate analysis included thoracic lymph node (LN) involvement and size of largest lung nodule ≥2 cm. Adjuvant chemotherapy and whether lung metastasis was detected synchronous or metachronous to liver metastasis had no influence on survival. In multivariate analysis, thoracic LN involvement emerged as the only independent factor (hazard ratio 4.86, 95 % confidence interval 1.56-15.14, p = 0.006). CONCLUSIONS PM offers a chance for long-term survival in selected patients with CRC and previously resected liver metastasis. Thoracic LN involvement predicted poor prognosis; therefore, significant efforts should be undertaken for adequate staging of the mediastinum before PM. In addition, adequate intraoperative LN sampling allows proper prognostic stratification and enrollment in novel adjuvant therapy trials.
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Affiliation(s)
- Samer Salah
- Medical Oncology Department, King Hussein Cancer Center, Amman, Jordan,
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12
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Andrea C, Fausto P, Francesca BK, Mary C, Mara G, Veronica L, Sandro B. Which strategy after first-line therapy in advanced colorectal cancer? World J Gastroenterol 2014; 20:8921-8927. [PMID: 25083064 PMCID: PMC4112862 DOI: 10.3748/wjg.v20.i27.8921] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2013] [Revised: 12/31/2013] [Accepted: 04/03/2014] [Indexed: 02/06/2023] Open
Abstract
Second-line therapy for advanced colorectal cancer is an integral part of the treatment strategy that needs to be set from the beginning for each patient, bearing in mind the expected toxicities of chosen treatments, the patient's clinical condition, comorbidities, preferences, the aims of the treatment and the molecular status. Furthermore, the distinction between lines of therapy is no longer absolute. The perspective of “continuum of care” includes switching chemotherapy prior to disease progression, maintenance therapy, drug "holidays" if needed, surgical resection of metastases in selected patients, and seems to allow a tailored treatment, in which patients are more likely to benefit from exposure to all active agents, which is known to correlate with overall survival. The scenario of second-line treatment has changed dramatically over the years and could currently benefit from several options including chemotherapy with a single agent or in combination and the addition of molecular-targeted agents developed in the last decade, such as epidermal growth factor receptor antibodies (cetuximab, panitumumab) and vascular endothelial growth factor-targeting agents (bevacizumab, aflibercept), with the possibility of bevacizumab use even beyond first progression. The purpose of this review is to summarize the most important scientific data supporting the use of chemotherapy and the new biologic agents in the second-line setting in advanced colorectal cancer.
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13
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Safety and efficacy of second-line treatment with folinic acid, 5-fluorouracil and irinotecan (FOLFIRI) in combination of panitumumab and bevacizumab for patients with metastatic colorectal cancer. Med Oncol 2014; 31:35. [DOI: 10.1007/s12032-014-0035-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2014] [Accepted: 05/10/2014] [Indexed: 10/25/2022]
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14
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Kim JH, Park SJ, Park MI, Moon W, Kim SE, Ku KH, Song SE, Kim JH. FOLFIRI as second-line chemotherapy after failure of FOLFOX4 in advanced colorectal cancer: a Korean single-center experience. THE KOREAN JOURNAL OF GASTROENTEROLOGY = TAEHAN SOHWAGI HAKHOE CHI 2014; 63:18-24. [PMID: 24463284 DOI: 10.4166/kjg.2014.63.1.18] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
BACKGROUND/AIMS The incidence of colorectal cancer has been increasing every year in Korea. Irinotecan- or oxaliplatin-based regimens including biologic agents are known to be effective in patients with advanced colorectal cancer. But in practice, FOLFOX (combination of oxaliplatin, 5-fluorouracil, and leucovorin) or FOLFIRI (combination of irinotecan, 5-fluorouracil, and leucovorin) regimens without biologic agents are more commonly used in Korea due to of the high costs of biologic agents. The aim of this study was to evaluate the efficacy and toxicity of FOLFIRI following FOLFOX4 in patients with advanced colorectal cancer. METHODS A total of 54 patients with advanced colorectal cancer who were treated between May 2005 and May 2013 with FOLFOX4 as first-line chemotherapy and with FOLFIRI as second-line chemotherapy at Kosin University Gospel Hospital (Busan, Korea) were reviewed retrospectively. RESULTS A total of 54 patients received second-line FOLFIRI chemotherapy. Five patients (9.3%) had a partial response, 29 patients (53.7%) had a stable disease. The median overall survival was 8.90 months and the median time to progression was 4.33 months. Toxicities were tolerable. CONCLUSIONS In a Korean population, FOLFIRI as second-line chemotherapy is effective and well tolerated in patients with advanced colorectal cancer after failure of FOLFOX4. Although the efficacy of FOLFIRI in this study was lower than that of second-line FOLFIRI with biologic agents, these results can help in the formulation of a treatment strategy for financially troubled patients.
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Affiliation(s)
- Jae Hyun Kim
- Division of Gastroenterology, Department of Internal Medicine, Kosin University College of Medicine, 262 Gamcheon-ro, Seo-gu, Busan 602-702, Korea
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Paulmurugan R, Oronsky B, Brouse CF, Reid T, Knox S, Scicinski J. Real time dynamic imaging and current targeted therapies in the war on cancer: a new paradigm. Theranostics 2013; 3:437-47. [PMID: 23781290 PMCID: PMC3677414 DOI: 10.7150/thno.5658] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2012] [Accepted: 02/28/2013] [Indexed: 12/13/2022] Open
Abstract
In biology, as every science student is made to learn, ontology recapitulates phylogeny. In medicine, however, oncology recapitulates polemology, the science of warfare: The medical establishment is transitioning from highly toxic poisons that kill rapidly dividing normal and malignant cells with little specificity to tailored therapies that target the tumors with the lethality of the therapeutic warhead. From the advent of the information age with the incorporation of high-tech intelligence, reconnaissance, and surveillance has resulted in "data fusion" where a wide range of information collected in near real-time can be used to redesign most of the treatment strategies currently used in the clinic. The medical community has begun to transition from the 'black box' of tumor therapy based solely on the clinical response to the 'glass box' of dynamic imaging designed to bring transparency to the clinical battlefield during treatment, thereby informing the therapeutic decision to 'retreat or repeat'. The tumor microenvironment is dynamic, constantly changing in response to therapeutic intervention, and therefore the therapeutic assessment must map to this variable and ever-changing landscape with dynamic and non-static imaging capabilities. The path to personalized medicine will require incorporation and integration of dynamic imaging at the bedside into clinical practice for real-time, interactive assessment of response to targeted therapies. The application of advanced real time imaging techniques along with current molecularly targeted anticancer therapies which alter cellular homeostasis and microenvironment can enhance therapeutic interventions in cancer patients and further improve the current status in clinical management of patients with advanced cancers.
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