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Rosati G, Piccirillo MC, Nasti G, De Stefano A, Carlomagno C, Romano C, Cassata A, Silvestro L, Nappi A, Perrone F, Budillon A, Avallone A. A Post Hoc Analysis of Older Patients with Metastatic Colorectal Cancer Receiving Oxaliplatin-Based Chemotherapy Plus Bevacizumab: The Randomized Obelics Study. Drugs Aging 2025; 42:353-362. [PMID: 40089969 DOI: 10.1007/s40266-025-01191-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/17/2025] [Indexed: 03/18/2025]
Abstract
BACKGROUND Phase II trials and subgroup analyses of clinical studies suggest that bevacizumab plus an oxaliplatin-based chemotherapy doublet is effective and tolerable in fit older patients with metastatic colorectal cancer (mCRC). OBJECTIVE To evaluate the influence of age on the incidence of side effects and efficacy of this combination in patients with mCRC randomized in the prospective phase III OBELICS study. METHODS In total, 230 patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 out of 1 were retrieved on the basis of age (190 < 70 years and 40 ≥ 70 years). They received bevacizumab 5 mg/kg administered either on the same day as chemotherapy (standard arm) or 4 days before chemotherapy (experimental arm) and oxaliplatin 85 mg/m2 on day 1, plus capecitabine 1000 mg/m2 twice a day (bid) orally on days 1-10 or levofolinic acid, 200 mg/m2, bolus 5-fluorouracil (5-FU) 400 mg/m2, and a 46-h intravenous infusion of 5-FU 2400 mg/m2, every 14 days; oxaliplatin was discontinued after 12 cycles. The primary end point was the overall response rate (ORR). RESULTS Efficacy and toxicity analyses are reported in aggregate form because there were no statistically significant differences between the two arms. Patient characteristics are well balanced between older and younger patients. No difference in ORR was observed between the two groups (50% for the older patients versus 57.9% for the younger ones; p = 0.36). The median PFS was 10.8 (95% confidence interval [CI], 9.9-12.2) and 11.3 (95% CI 8.3-13.0) months, respectively, for subjects younger than 70 years and those aged ≥ 70 years, with an adjusted hazard ratio (HR) of 1.16 (95% CI 0.80-1.68; p = 0.43). The median OS was 26.2 (95% CI 23.3-32.7) for the former and 23.2 (95% CI 17.3-35.3) months for the latter, respectively, with an adjusted HR of 1.60 (95% CI 1.08-2.37; p = 0.027). Considering all forms of toxicity, the most severe ones were not statistically different between the two groups (65% for the older patients and 60.6% for the younger ones, p = 0.61). CONCLUSIONS Bevacizumab plus an oxaliplatin-based chemotherapy doublet were effective in older patients randomized in the OBELICS trial, and the adverse event profile was not dissimilar from that of younger patients; no new safety concerns were identified. This post hoc analysis confirms that fit older patients with mCRC should be considered for treatment with this regimen.
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Affiliation(s)
- Gerardo Rosati
- Medical Oncology Unit, S. Carlo Hospital, Potenza, Italy.
| | | | - Guglielmo Nasti
- Innovative Therapy for Abdominal Metastases-IRCCS-Fondazione G. Pascale, Naples, Italy
| | - Alfonso De Stefano
- Experimental Clinical Abdominal Oncology Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Via Mariano Semmola, 53, 80131, Naples, Italy
| | - Chiara Carlomagno
- Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy
| | - Carmela Romano
- Experimental Clinical Abdominal Oncology Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Via Mariano Semmola, 53, 80131, Naples, Italy
| | - Antonino Cassata
- Experimental Clinical Abdominal Oncology Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Via Mariano Semmola, 53, 80131, Naples, Italy
| | - Lucrezia Silvestro
- Experimental Clinical Abdominal Oncology Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Via Mariano Semmola, 53, 80131, Naples, Italy
| | - Anna Nappi
- Experimental Clinical Abdominal Oncology Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Via Mariano Semmola, 53, 80131, Naples, Italy
| | - Franco Perrone
- Clinical Trials Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples, Italy
| | - Alfredo Budillon
- Experimental Pharmacology Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples, Italy
| | - Antonio Avallone
- Experimental Clinical Abdominal Oncology Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Via Mariano Semmola, 53, 80131, Naples, Italy.
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Vonica RC, Butuca A, Morgovan C, Pumnea M, Cipaian RC, Frum A, Dobrea CM, Vonica-Tincu AL, Pacnejer AM, Ghibu S, Batar F, Gligor FG. Bevacizumab-Insights from EudraVigilance Database on the Assessments of the Safety Profile of Monoclonal Antibodies Used as Targeted Cancer Treatment. Pharmaceuticals (Basel) 2025; 18:501. [PMID: 40283938 PMCID: PMC12030381 DOI: 10.3390/ph18040501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2025] [Revised: 03/22/2025] [Accepted: 03/27/2025] [Indexed: 04/29/2025] Open
Abstract
Background/Objectives: Worldwide, colon cancer is a major cause of cancer-related mortality, with an increasing incidence influenced by genetic, environmental, and lifestyle factors. Despite advances in diagnosis and personalized treatments, challenges remain in improving patient prognosis, particularly in metastatic colorectal cancer (mCRC). Bevacizumab (BEV), a monoclonal antibody, is widely used in colorectal cancer treatment. This study aimed to analyze adverse events associated with BEV compared with other therapies based on data from the EudraVigilance (EV) database. Methods: A descriptive and disproportionality analysis was conducted on signals reported in the EV database related to BEV. The study included comparisons with other antineoplastic treatments, such as chemotherapy, targeted therapy, and immunotherapy. Patient demographics, severity of adverse drug reactions (ADRs), and distribution patterns were analyzed to assess the safety profile of BEV in colorectal cancer treatment. Results: The majority of the signals for BEV were from patients aged 18-64 years (39.42%) and 65-85 years (34.08%). Hypertension, thromboembolism, proteinuria, and gastrointestinal disorders have been the most frequently reported. Serious ADRs, including gastrointestinal perforations, hemorrhage, and arterial thromboembolism, were observed in 93.74% of Individual Case Safety Reports. BEV was associated with a higher likelihood of vascular and endocrine disorders compared with chemotherapy and other targeted therapies. Immunotherapy was linked to increased immunological ADRs, while BEV demonstrated fewer immune-related toxicities. Conclusions: Continuous monitoring is necessary to optimize patient management, particularly in elderly patients or those with cardiovascular comorbidities. Understanding BEV's safety profile allows for better personalization of treatment strategies, minimizing risks while enhancing therapeutic outcomes.
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Affiliation(s)
- Razvan Constantin Vonica
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
| | - Anca Butuca
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
| | - Claudiu Morgovan
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
| | - Manuela Pumnea
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
| | - Remus Calin Cipaian
- Clinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania;
- County Clinical Emergency Hospital of Sibiu, 2–4 Corneliu Coposu Str., 550245 Sibiu, Romania
| | - Adina Frum
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
| | - Carmen Maximiliana Dobrea
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
| | - Andreea Loredana Vonica-Tincu
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
| | - Aliteia-Maria Pacnejer
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
- Department of Toxicology, Drug Industry, Management and Legislation, Faculty of Pharmacy, “Victor Babeş” University of Medicine and Pharmacy, 2nd Eftimie Murgu Sq., 300041 Timişoara, Romania
| | - Steliana Ghibu
- Department of Pharmacology, Physiology and Pathophysiology, Faculty of Pharmacy, “Iuliu Haţieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania;
| | - Florina Batar
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
| | - Felicia Gabriela Gligor
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
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Zheng E, Włodarczyk M, Węgiel A, Osielczak A, Możdżan M, Biskup L, Grochowska A, Wołyniak M, Gajewski D, Porc M, Maryńczak K, Dziki Ł. Navigating through novelties concerning mCRC treatment-the role of immunotherapy, chemotherapy, and targeted therapy in mCRC. Front Surg 2024; 11:1398289. [PMID: 38948479 PMCID: PMC11211389 DOI: 10.3389/fsurg.2024.1398289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Accepted: 05/29/2024] [Indexed: 07/02/2024] Open
Abstract
Over the course of nearly six decades since the inception of initial trials involving 5-FU in the treatment of mCRC (metastatic colorectal cancer), our progressive comprehension of the pathophysiology, genetics, and surgical techniques related to mCRC has paved the way for the introduction of novel therapeutic modalities. These advancements not only have augmented the overall survival but have also positively impacted the quality of life (QoL) for affected individuals. Despite the remarkable progress made in the last two decades in the development of chemotherapy, immunotherapy, and target therapies, mCRC remains an incurable disease, with a 5-year survival rate of 14%. In this comprehensive review, our primary goal is to present an overview of mCRC treatment methods following the latest guidelines provided by the National Comprehensive Cancer Network (NCCN), the American Society of Clinical Oncology (ASCO), and the American Society of Colon and Rectal Surgeons (ASCRS). Emphasis has been placed on outlining treatment approaches encompassing chemotherapy, immunotherapy, targeted therapy, and surgery's role in managing mCRC. Furthermore, our review delves into prospective avenues for developing new therapies, offering a glimpse into the future of alternative pathways that hold potential for advancing the field.
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Affiliation(s)
- Edward Zheng
- Department of General and Oncological Surgery, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Marcin Włodarczyk
- Department of General and Oncological Surgery, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Andrzej Węgiel
- Department of General and Oncological Surgery, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Aleksandra Osielczak
- Department of General and Oncological Surgery, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Maria Możdżan
- Department of General and Oncological Surgery, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Laura Biskup
- Department of General and Oncological Surgery, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Agata Grochowska
- Department of General and Oncological Surgery, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Maria Wołyniak
- Department of General and Oncological Surgery, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, Lodz, Poland
| | - Dominik Gajewski
- Department of General and Oncological Surgery, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Mateusz Porc
- Department of General and Oncological Surgery, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Kasper Maryńczak
- Department of General and Oncological Surgery, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Łukasz Dziki
- Department of General and Oncological Surgery, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
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Zhang KD, Jost E, Panse J, Herwartz R, Lindemann-Docter K, Jonigk D, Kricheldorf K, Köchel A, Sauerbrunn N, Brümmendorf TH, Koschmieder S, Isfort S. Bone marrow biopsy in geriatric patients above the age of 85 years: invaluable or unnecessary? A retrospective analysis. Ann Hematol 2024; 103:1149-1158. [PMID: 38336973 PMCID: PMC10940467 DOI: 10.1007/s00277-024-05650-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 01/31/2024] [Indexed: 02/12/2024]
Abstract
Bone marrow biopsy (BMB) is a well-established diagnostic tool for various hematological, oncological, and other medical conditions. However, treatment options for geriatric patients (pts) facing these diseases are often constrained. In this single-center, retrospective analysis we assessed the diagnostic value of BMB in geriatric pts aged ≥ 85 years and examined its impact on therapeutic decisions. We examined 156 BMB procedures in 129 pts, extracting data from the electronic patient records and applying descriptive statistical methods. Nearly half of the primary diagnostic procedures (26; 44.1%) resulted in a modification of the initially suspected diagnosis. Notably, 15 (25.4%) of these procedures, led to changes in both the diagnosis and planned interventional treatment. Among the 15 follow-up procedures (36.6%), disease progression was initially suspected based on symptoms, but BMB results excluded such progression. In lymphoma staging biopsies, only 2 (3.6%) prompted a change in therapeutic intervention. Importantly, no BMB-related complications, such as bleeding, infection or nerve damage, were reported. Median survival after BMB was 16.1 months across all pts, yet it varied based on the diagnosis and comorbidity score. The survival of pts with a change in therapy based on BMB results did not significantly differ from those who did not undergo a therapy change. In conclusion, BMB proved to be generally safe and beneficial in this geriatric cancer patient cohort beyond the age of 85 years. However, the advantages of lymphoma staging in this patient population warrant further consideration.
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Affiliation(s)
- Kailun David Zhang
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany
- Center for Integrated Oncology, Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany
- Department of Neurology, Kliniken Maria Hilf Mönchengladbach, Mönchengladbach, Germany
| | - Edgar Jost
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany
- Center for Integrated Oncology, Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany
| | - Jens Panse
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany
- Center for Integrated Oncology, Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany
| | - Reinhild Herwartz
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany
- Center for Integrated Oncology, Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany
| | - Katharina Lindemann-Docter
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany
- Center for Integrated Oncology, Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany
- German Center for Lung Research (DZL), BREATH, Hannover, Germany
| | - Danny Jonigk
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany
- Center for Integrated Oncology, Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany
- German Center for Lung Research (DZL), BREATH, Hannover, Germany
| | - Kim Kricheldorf
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany
- Center for Integrated Oncology, Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany
| | - Anja Köchel
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany
- Center for Integrated Oncology, Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany
| | - Nicolas Sauerbrunn
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany
- Center for Integrated Oncology, Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany
| | - Tim H Brümmendorf
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany
- Center for Integrated Oncology, Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany
| | - Steffen Koschmieder
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany
- Center for Integrated Oncology, Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany
| | - Susanne Isfort
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany.
- Center for Integrated Oncology, Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany.
- Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Medical School Hannover, Hannover, Germany.
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Toquero P, Mondéjar R, Romero-Laorden N, Méndez E, Castillo L, Hernández Marín B, Donnay O, Colomer R. Is Older Age an Independent Prognostic Factor of Survival in Metastatic Colorectal Cancer? Oncology 2024; 102:747-758. [PMID: 38232719 DOI: 10.1159/000535187] [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: 09/18/2023] [Accepted: 11/03/2023] [Indexed: 01/19/2024]
Abstract
INTRODUCTION Older patients (≤75 years) with advanced colorectal cancer (CRC) may have worse survival than non-older patients. We hypothesized that, rather than age alone, concurrent factors may be more relevant for real-world survival. METHODS Patients diagnosed with CRC in a 5-year period (2014-2018) were analyzed to determine which factors influenced in overall survival (OS). Kaplan-Meier method was used to estimate OS. Univariate and multivariate analysis was conducted by Cox regression analysis. The study was approved by Ethics Committee. RESULTS Out of 477 patients diagnosed with CRC, 231 had advanced disease. Ninety-two patients (40%) were older than 75 years; median OS (mOS) was 17.1 m (95% CI: 14.3-23.3), p < 0.001. In non-older patients, mOS was 26.7 m (95% CI: 21.9-32.6), p < 0.001. We evaluated eighteen concurrent factors that included characteristics related to the patient (age, sex, comorbidities, polypharmacy, Eastern Cooperative Oncology Group (ECOG), and nutritional status), to the tumor (stage at diagnosis, tumor side, molecular profile, tumor burden, location, and number of metastasis), and to the treatment administered (systemic treatment for advanced disease, chemotherapy schedule and number of lines, severe adverse events and dose reductions, and surgery of liver metastasis). In the univariate analysis, age at diagnosis, ECOG, nutritional status, tumor side, molecular profile, tumor burden, systemic treatment for advanced disease, and surgery of liver metastases had significant impact on survival. However, multivariate analysis revealed that only four factors (tumor burden, nutritional status, systemic treatment for advanced disease, and surgery of liver metastases) were independently associated with OS but not older age at diagnosis. CONCLUSION Older age is not an independent survival prognostic factor for advanced CRC. Tumor burden, nutritional status, systemic treatment for advanced disease, and surgery of liver metastasis were significant factors associated with OS. These findings suggest that older patients should not be excluded from cancer treatment based on age alone.
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Affiliation(s)
- Patricia Toquero
- Medical Oncology Department, La Princesa University Hospital, Madrid, Spain
- Precision Medicine Chair, Medical Oncology Department, Universidad Autónoma de Madrid - Roche Institute Foundation- Hospital Universitario de La Princesa, Madrid, Spain
| | - Rebeca Mondéjar
- Medical Oncology Department, La Princesa University Hospital, Madrid, Spain
- Precision Medicine Chair, Medical Oncology Department, Universidad Autónoma de Madrid - Roche Institute Foundation- Hospital Universitario de La Princesa, Madrid, Spain
| | - Nuria Romero-Laorden
- Medical Oncology Department, La Princesa University Hospital, Madrid, Spain
- Precision Medicine Chair, Medical Oncology Department, Universidad Autónoma de Madrid - Roche Institute Foundation- Hospital Universitario de La Princesa, Madrid, Spain
| | - Elena Méndez
- Medical Oncology Department, Henares University Hospital, Coslada, Spain
| | - Lucía Castillo
- Medical Oncology Department, La Princesa University Hospital, Madrid, Spain
| | - Berta Hernández Marín
- Medical Oncology Department, La Princesa University Hospital, Madrid, Spain
- Precision Medicine Chair, Medical Oncology Department, Universidad Autónoma de Madrid - Roche Institute Foundation- Hospital Universitario de La Princesa, Madrid, Spain
| | - Olga Donnay
- Medical Oncology Department, La Princesa University Hospital, Madrid, Spain
| | - Ramon Colomer
- Medical Oncology Department, La Princesa University Hospital, Madrid, Spain
- Precision Medicine Chair, Medical Oncology Department, Universidad Autónoma de Madrid - Roche Institute Foundation- Hospital Universitario de La Princesa, Madrid, Spain
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Soler-González G, Sastre-Valera J, Viana-Alonso A, Aparicio-Urtasun J, García-Escobar I, Gómez-España MA, Guillén-Ponce C, Molina-Garrido MJ, Gironés-Sarrió R. Update on the management of elderly patients with colorectal cancer. Clin Transl Oncol 2024; 26:69-84. [PMID: 37498507 PMCID: PMC10761480 DOI: 10.1007/s12094-023-03243-0] [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: 05/03/2023] [Accepted: 05/31/2023] [Indexed: 07/28/2023]
Abstract
Colorectal cancer (CRC) is one of the most common tumours worldwide, and 70% of CRC patients are over 65 years of age. However, the scientific evidence available for these patients is poor, as they are underrepresented in clinical trials. Therefore, a group of experts from the Oncogeriatrics Section of the Spanish Society of Medical Oncology (SEOM), the Spanish Cooperative Group for the Treatment of Digestive Tumours, (TTD) and the Multidisciplinary Spanish Group of Digestive Cancer (GEMCAD) have reviewed the scientific evidence available in older patients with CRC. This group of experts recommends a multidisciplinary approach and geriatric assessment (GA) before making a therapeutic decision because GA predicts the risk of toxicity and survival and helps to individualize treatment. In addition, elderly patients with localized CRC should undergo standard cancer resection, preferably laparoscopically. The indication for adjuvant chemotherapy (CT) should be considered based on the potential benefit, the risk of recurrence, the life expectancy and patient comorbidities. When the disease is metastatic, the possibility of radical treatment with surgery, radiofrequency (RF) or stereotactic body radiation therapy (SBRT) should be considered. The efficacy of palliative CT is similar to that seen in younger patients, but elderly patients are at increased risk of toxicity. Clinical trials should be conducted with the elderly population and include GAs and specific treatment plans.
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Affiliation(s)
- Gemma Soler-González
- Departamento de Oncología Médica, Spanish Society of Medical Oncology (SEOM) Oncogeriatrics Section, Institut Català d'Oncologia (ICO) L'Hospitalet, Avinguda de la Granvia de l'Hospitalet 199-203, L'Hospitalet de Llobregat, 08908, Barcelona, Spain.
| | - Javier Sastre-Valera
- Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD), Clinico San Carlos University Hospital, Madrid, Spain
| | - Antonio Viana-Alonso
- Spanish Society of Medical Oncology (SEOM) Oncogeriatrics Section, Nuestra Señora del Prado General University Hospital, Talavera de la Reina, Spain
| | - Jorge Aparicio-Urtasun
- Multidisciplinary Spanish Group of Digestive Cancer (GEMCAD), Polytechnic la Fe University Hospital, Valencia, Spain
| | - Ignacio García-Escobar
- Spanish Society of Medical Oncology (SEOM) Oncogeriatrics Section, General University Hospital of Toledo, Toledo, Spain
| | - María Auxiliadora Gómez-España
- Spanish Society of Medical Oncology (SEOM) Oncogeriatrics Section, Reina Sofía University Hospital. Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
| | - Carmen Guillén-Ponce
- Spanish Society of Medical Oncology (SEOM) Oncogeriatrics Section, Ramón y Cajal University Hospital, Madrid, Spain
| | - María José Molina-Garrido
- Spanish Society of Medical Oncology (SEOM) Oncogeriatrics Section, Virgen de la Luz Hospital, Cuenca, Spain
| | - Regina Gironés-Sarrió
- Spanish Society of Medical Oncology (SEOM) Oncogeriatrics Section, Polytechnic la Fe University Hospital, Valencia, Spain
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Chitkara A, Kaur N, Desai A, Mehta D, Anamika F, Sarkar S, Gowda N, Sethi P, Thawani R, Chen EY. Risks of hypertension and thromboembolism in patients receiving bevacizumab with chemotherapy for colorectal cancer: A systematic review and meta-analysis. Cancer Med 2023; 12:21579-21591. [PMID: 38069531 PMCID: PMC10757147 DOI: 10.1002/cam4.6662] [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: 05/22/2023] [Revised: 09/12/2023] [Accepted: 10/03/2023] [Indexed: 12/31/2023] Open
Abstract
BACKGROUND Guidelines show that for metastatic colorectal cancer (mCRC), a combination of three-drug regimens, fluorouracil, leucovorin, and oxaliplatin and bevacizumab (BVZ), is one of the first-line standard therapies. BVZ is generally well tolerated; however, it is associated with infrequent, life-threatening side effects such as severe hypertension (HTN) (5%-18%), Grade ≥3 arterial thromboembolism (ATE) (2.6%), Grade ≥3 hemorrhagic events (1.2%-4.6%), and gastrointestinal perforation (0.3%-2.4%). This meta-analysis aims to evaluate the additive risk of BVZ-induced severe HTN and thromboembolism when BVZ is combined with a standard chemotherapy regime in patients with mCRC. METHODS Our search was conducted from January 29, 2022, to February 22, 2022, through databases of PubMed, clinicaltrial.gov, EMBASE, Web of Science, and Cochrane Library. Data analysis from randomized controlled trials (RCTs) and clinical trials was conducted using Review Manager V.5.4, comparing BVZ-chemotherapy to chemotherapy only, focusing on cardiovascular AE such as HTN and arterial and venous thromboembolism. RESULTS The analysis from 26 clinical trials and RCTs showed that the odds of HTN were about four times higher, and ATE subgroup analysis of 11 studies showed over two times higher odds of ATE in patients being treated with BVZ compared to the chemotherapy-only group. CONCLUSION BVZ, when added to the standard chemotherapy regimen for mCRC, was associated with higher odds of developing HTN and thromboembolism, specifically ATE, than the chemotherapy-only group. Our findings are significant as they provide vital information in analyzing the risk-benefit ratio of adding BVZ to the standard chemotherapy regime in patients with mCRC, especially in patients with vascular comorbidities.
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Affiliation(s)
- Akshit Chitkara
- Internal MedicineUniversity of California RiversideRiversideCaliforniaUSA
| | - Nirmaljot Kaur
- Internal MedicineUniversity of California RiversideRiversideCaliforniaUSA
| | - Aditya Desai
- Internal MedicineUniversity of California RiversideRiversideCaliforniaUSA
| | - Devanshi Mehta
- Loma Linda UniversityCalifornia in Internal MedicineCaliforniaUSA
| | - Fnu Anamika
- Internal MedicineHackensack Meridian Ocean UniversityBrickNew JerseyUSA
| | - Srawani Sarkar
- Research LabAlbert Einstein College of MedicineNew YorkNew YorkUSA
| | - Nandini Gowda
- Internal MedicineUniversity of California RiversideRiversideCaliforniaUSA
| | - Prabhdeep Sethi
- Internal MedicineUniversity of California RiversideRiversideCaliforniaUSA
| | - Rajat Thawani
- Division of Hematology and Medical Oncology, Knight Cancer InstituteOregon Health & Sciences UniversityPortlandOregonUSA
| | - Emerson Y. Chen
- Division of Hematology and Medical Oncology, Knight Cancer InstituteOregon Health & Sciences UniversityPortlandOregonUSA
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8
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NODA M, INAJI M, KARAKAMA J, ARAI Y, KUROHA M, TAMURA K, TANAKA Y, MAEHARA T. Ischemic Stroke with Multiple Cerebral Artery Stenosis in a Patient with an Anaplastic Astrocytoma during Bevacizumab Treatment: A Case Report. NMC Case Rep J 2022; 9:13-17. [PMID: 35340332 PMCID: PMC8906840 DOI: 10.2176/jns-nmc.2021-0297] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 12/14/2021] [Indexed: 11/20/2022] Open
Abstract
It has been reported that bevacizumab, an agent administered as an adjuvant therapy for high-grade gliomas, causes thromboembolic complications. We report a cerebral infarction with newly developed cerebral artery stenosis occurring during treatment with bevacizumab for an anaplastic astrocytoma. A 48-year-old female underwent excision surgery for an anaplastic astrocytoma on the right temporal lobe and received radiation therapy and chemotherapy with temozolomide. Twenty months after the maintenance therapy, treatment with bevacizumab was introduced for tumor recurrence. After the 14th course of bevacizumab at 6 months, 27 months after radiation therapy, the patient began experiencing mild right hemiparesis. Magnetic resonance imaging revealed scattered cerebral infarcts on the left frontal lobe and diffuse cerebral artery stenosis of the bilateral internal carotid artery system both inside and outside the radiation-treated area. Antiplatelet medication was commenced, and there was no recurrence of ischemic stroke. The morphological transition of the cerebral arteries should be carefully monitored via magnetic resonance angiography during post-radiation treatment with bevacizumab.
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Affiliation(s)
- Mariko NODA
- Department of Neurosurgery, Tokyo Medical and Dental University
| | - Motoki INAJI
- Department of Neurosurgery, Tokyo Medical and Dental University
| | - Jun KARAKAMA
- Department of Neurosurgery, Tokyo Medical and Dental University
| | - Yukika ARAI
- Department of Neurosurgery, Tokyo Medical and Dental University
| | - Masae KUROHA
- Department of Neurosurgery, Tokyo Medical and Dental University
| | - Kaoru TAMURA
- Department of Neurosurgery, Tokyo Medical and Dental University
| | - Yoji TANAKA
- Department of Neurosurgery, Tokyo Medical and Dental University
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9
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Jang HR, Lee HY, Song SY, Lim KH. Clinical outcomes of targeted therapies in elderly patients aged ≥ 80 years with metastatic colorectal cancer. World J Clin Cases 2022; 10:10066-10076. [PMID: 36246797 PMCID: PMC9561573 DOI: 10.12998/wjcc.v10.i28.10066] [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] [Received: 06/07/2022] [Revised: 07/26/2022] [Accepted: 08/17/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND The 5-fluorouracil-based chemotherapy combined with oxaliplatin or irinotecan is usually used in colorectal cancer (CRC). The addition of a targeted agent (TA) to this combination chemotherapy is currently the standard treatment for metastatic CRC. However, the efficacy and safety of combination chemotherapy for metastatic CRC in patients aged above 80 years has yet to be established.
AIM To assess the clinical outcomes and feasibility of combination chemotherapy using a TA in extremely elderly patients with CRC.
METHODS Eligibility criteria were: (1) Age above 80 years; (2) Metastatic colorectal cancer; (3) Palliative chemotherapy naïve; (4) Eastern Cooperative Oncology Group performance status 0-1; and (5) Adequate organ function. Patients received at least one dose of combination chemotherapy with or without TA. Response was evaluated every 8 wk.
RESULTS Of 30 patients, the median age of 15 patients treated with TA was 83.0 years and that of those without TA was 81.3 years. The median progression-free survival (PFS) and overall survival (OS) in patients treated with TA were 7.4 mo and 15.4 mo, respectively, compared with 4.4 mo and 15.6 mo, respectively, in patients treated without TA. There was no significant difference in PFS (P: 0.193) and OS (P: 0.748) between patients treated with and without TA. Common grade 3/4 hematologic toxicities were anemia (16.7%) and neutropenia (10.0%). After disease progression, the median OS of patients who were treated with and without salvage chemotherapy were 23.5 mo and 7.0 mo, respectively, suggesting significant difference in OS (P = 0.001).
CONCLUSION Combination chemotherapy with TA for metastatic CRC may be considered feasible in patients aged above 80 years, when with careful caution. Salvage chemotherapy can help improve OS in some selected of these elderly patients.
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Affiliation(s)
- Hee Ryeong Jang
- Department of Internal Medicine, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon-si, Gangwon-do 24289, South Korea
| | - Hui-Young Lee
- Department of Internal Medicine, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon-si, Gangwon-do 24289, South Korea
| | - Seo-Young Song
- Department of Internal Medicine, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon-si, Gangwon-do 24289, South Korea
| | - Kyu-Hyoung Lim
- Department of Internal Medicine, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon-si, Gangwon-do 24289, South Korea
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10
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Stahler A, Modest DP, Fischer von Weikersthal L, Kaiser F, Decker T, Held S, Graeven U, Schwaner I, Denzlinger C, Schenk M, Kurreck A, Heinrich K, Gießen-Jung C, Neumann J, Kirchner T, Jung A, Stintzing S, Heinemann V. First-line fluoropyrimidine plus bevacizumab followed by irinotecan-escalation versus initial fluoropyrimidine, irinotecan and bevacizumab in patients with metastatic colorectal cancer - Final survival and per-protocol analysis of the randomised XELAVIRI trial (AIO KRK 0110). Eur J Cancer 2022; 173:194-203. [PMID: 35940054 DOI: 10.1016/j.ejca.2022.06.019] [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: 04/05/2022] [Revised: 06/03/2022] [Accepted: 06/09/2022] [Indexed: 11/24/2022]
Abstract
BACKGROUND The randomised open-label phase III XELAVIRI trial failed to demonstrate non-inferiority of the sequential application of fluoropyrimidine plus bevacizumab followed by additional irinotecan at first progression (Arm A) versus initial combination of all agents (Arm B) for untreated metastatic colorectal cancer in the initial analysis of time-to-failure-of-strategy (TFS, 90% confidence boundary of 0.8). Here, we evaluate efficacy in the full analysis set (FAS), the per-protocol set, in addition to age-related and molecular subgroups. METHODS Median TFS, overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier method and log-rank test. Cox regression models assessed hazard ratios (HRs) and confidence intervals (CIs) (TFS: 90%; OS, PFS: 95%). RESULTS Of 421 patients, 390 (92.6%), 391 (92.9%) and 357 (84.8%) events for TFS, OS and PFS were observed in the FAS with a median follow-up of 54.2 months (Arm A) versus 52.9 months (Arm B). Non-inferiority of sequential treatment for TFS was missed in the FAS (HR 0.93; 90% CI, 0.79-1.10; P = 0.482) and not shown in the per-protocol set (HR 0.93; 90% CI, 0.75-1.13, P = 0.433). Formal non-inferiority for TFS was observed for patients older than 70 years (HR 1.06; 90% CI, 0.80-1.41; P = 0.670) and patients with RAS mutant tumours (HR 1.12; 90% CI, 0.87-1.43; P = 0.465). In RAS/BRAF wild-type tumours, combination treatment was significantly superior to sequential therapy in all end-points. CONCLUSIONS In the overall population, XELAVIRI just missed to demonstrate the non-inferiority of sequential compared to combination therapy for TFS. However, the non-inferiority of sequential treatment was observed in elderly patients and RAS mutant tumours. TRIAL REGISTRATION Trial registration ID (clinicaltrials.gov) NCT01249638.
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Affiliation(s)
- Arndt Stahler
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology, and Cancer Immunology, Charitéplatz 1, 10117 Berlin, Germany.
| | - Dominik P Modest
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology, and Cancer Immunology, Charitéplatz 1, 10117 Berlin, Germany; Charité - Universitätsmedizin, German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | | | | | | | | | | | - Ingo Schwaner
- Onkologische Schwerpunktpraxis Kurfürstendamm, Berlin, Germany
| | | | - Michael Schenk
- Krankenhaus Barmherzige Brüder Regensburg, Regensburg, Germany
| | - Annika Kurreck
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology, and Cancer Immunology, Charitéplatz 1, 10117 Berlin, Germany
| | - Kathrin Heinrich
- Department of Medicine III, University Hospital, LMU Munich, Germany
| | | | - Jens Neumann
- Institute of Pathology, Faculty of Medicine, LMU Munich, Germany; LMU Munich, German Cancer Consortium (DKTK), Partner Site Munich, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Thomas Kirchner
- Institute of Pathology, Faculty of Medicine, LMU Munich, Germany; LMU Munich, German Cancer Consortium (DKTK), Partner Site Munich, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Andreas Jung
- Institute of Pathology, Faculty of Medicine, LMU Munich, Germany; LMU Munich, German Cancer Consortium (DKTK), Partner Site Munich, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Sebastian Stintzing
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology, and Cancer Immunology, Charitéplatz 1, 10117 Berlin, Germany; Charité - Universitätsmedizin, German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Volker Heinemann
- Department of Medicine III, University Hospital, LMU Munich, Germany; LMU Munich, German Cancer Consortium (DKTK), Partner Site Munich, German Cancer Research Center (DKFZ), Heidelberg, Germany
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11
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Efficacy of FOLFIRI plus cetuximab vs FOLFIRI plus bevacizumab in 1st-line treatment of older patients with RAS wild-type metastatic colorectal cancer: an analysis of the randomised trial FIRE-3. Br J Cancer 2022; 127:836-843. [PMID: 35637412 PMCID: PMC9427779 DOI: 10.1038/s41416-022-01854-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 04/14/2022] [Accepted: 05/09/2022] [Indexed: 12/09/2022] Open
Abstract
Summary
Background
The evidence on the efficacy of anticancer therapy is limited in older patients with metastatic colorectal cancer (mCRC). This retrospective analysis of phase III FIRE-3 trial assesses the efficacy of FOLFIRI plus either cetuximab or bevacizumab according to the patients’ age and sidedness of primary tumour.
Methods
The study endpoints overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) were compared between younger (<65 years) and older (≥65 years) patients, followed by stratification according to primary tumour sidedness. ORR was compared using Fisher´s exact test, OS and PFS were estimated by the Kaplan–Meier method and compared using the log-rank test. Univariate Cox regression analyses assessed hazard ratios and 95% confidence intervals for OS and PFS.
Results
Overall, older patients with RAS WT tumours had a significantly shorter OS when compared to younger patients (25.9 months vs 29.3 months, HR 1.29; P = 0.02). Also the proportion of right-sided tumours was significantly greater in older patients (27.1% vs 17.9%; P = 0.029). Secondary resection rates were numerically higher in younger patients (25.4% vs. 17.6%, P = 0.068) than in older patients. This was primarily seen in the Cetuximab arm, where older patients underwent less likely resection (13.1% vs. 26%; P = 0.02). Older patients with left-sided tumours showed only a trend towards greater efficacy of cetuximab (HR 0.86; P = 0.38). In patients with right-sided primary tumours, older patients did not appear to benefit from cetuximab in contrast to younger patients (≥65 years: 16.6 months vs 23.6 months, HR 1.1; P = 0.87; <65 years: 21.9 months vs 16.4 months HR 1.5; P = 0.31).
Conclusions
In FIRE-3, OS was generally shorter in older patients in comparison to younger patients. This could be explained by the overrepresentation of right-sided tumours and a lower secondary resection rate in older patients. The efficacy of targeted therapy was dependent on tumour sidedness in older patients with RAS WT mCRC.
Clinical trial
FIRE-3 (NCT00433927).
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12
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Correa E, Lindsay T, Dotan E. Management of Metastatic Colorectal Carcinoma in Older Adults: Balancing Risks and Benefits of Novel Therapies. Drugs Aging 2021; 38:639-654. [PMID: 34143421 PMCID: PMC9951235 DOI: 10.1007/s40266-021-00869-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/22/2021] [Indexed: 11/25/2022]
Abstract
The prevalence of older patients with metastatic colorectal cancer (mCRC) will continue to increase with our aging population. Treatment of mCRC has changed significantly in the last few decades as we have learned how to personalize the treatment of mCRC to the biology of the tumor, utilizing new treatment approaches. With an ever-changing treatment paradigm, managing the population of older adults becomes paramount. This review highlights the pivotal clinical trials that defined the use of systemic therapy, immunotherapy and targeted therapies for mCRC, and how those are applied to the older patient population. In addition, we outline the tools for an in-depth assessment of an older adult in regards to treatment planning and management of therapy-related toxicities. A comprehensive geriatric assessment can assist in the selection of treatment for an older adult with mCRC. While frail older patients can frequently only tolerate single agents or modified regimens, fit older adults remain candidates for a wider range of treatment options. However, since all of these treatments are associated with possible toxicities, each patient's treatment must be personalized to the patient's goals and wishes through a shared decision-making process.
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Affiliation(s)
- Erika Correa
- Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Timothy Lindsay
- Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Efrat Dotan
- Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.
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13
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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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14
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Guarini C, Grassi T, Pezzicoli G, Porta C. Beyond RAS and BRAF: HER2, a New Actionable Oncotarget in Advanced Colorectal Cancer. Int J Mol Sci 2021; 22:6813. [PMID: 34202896 PMCID: PMC8268006 DOI: 10.3390/ijms22136813] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 06/21/2021] [Accepted: 06/22/2021] [Indexed: 12/31/2022] Open
Abstract
The human epidermal growth factor receptor 2 (HER2) is a well-established oncogenic driver and a successful therapeutic target in several malignancies, such as breast and gastric cancers. HER2 alterations, including amplification and somatic mutations, have also been detected in a small but not negligible subset of patients affected by advanced colorectal cancer (aCRC). However, to date, there are no available oncotargets in this malignancy beyond RAS and BRAF that are available. Here we present an overview on the present predictive and prognostic role of HER2 expression in aCRC, as well as on its consequent potential therapeutic implications from preclinical investigations towards ongoing trials testing anti-HER2 agents in aCRC. While HER2's role as a molecular predictive biomarker for anti-EGFR therapies in CRC is recognized, HER2 prognostic value remains controversial. Moreover, thanks to the impressive and growing body of clinical evidence, HER2 is strongly emerging as a new potential actionable oncotarget in aCRC. In conclusion, in the foreseeable future, HER2-targeted therapeutic strategies may integrate the algorithm of aCRC treatment towards an increasingly tailored therapeutic approach to this disease.
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Affiliation(s)
- Chiara Guarini
- Post-Graduate School of Specialization in Medical Oncology, University of Bari ‘Aldo Moro’, 70124 Bari, Italy;
- Division of Medical Oncology, A.O.U. Consorziale Policlinico di Bari, 70124 Bari, Italy; (T.G.); (C.P.)
| | - Teresa Grassi
- Division of Medical Oncology, A.O.U. Consorziale Policlinico di Bari, 70124 Bari, Italy; (T.G.); (C.P.)
| | - Gaetano Pezzicoli
- Post-Graduate School of Specialization in Medical Oncology, University of Bari ‘Aldo Moro’, 70124 Bari, Italy;
- Division of Medical Oncology, A.O.U. Consorziale Policlinico di Bari, 70124 Bari, Italy; (T.G.); (C.P.)
| | - Camillo Porta
- Division of Medical Oncology, A.O.U. Consorziale Policlinico di Bari, 70124 Bari, Italy; (T.G.); (C.P.)
- Chair of Oncology, Department of Biomedical Sciences and Human Oncology, University of Bari ‘A. Moro’, 70124 Bari, Italy
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15
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García-Alfonso P, Díaz-Rubio E, Abad A, Carrato A, Massutí B, Ortiz-Morales MJ, Manzano Mozo JL, Muñoz A, Durán G, Sastre J, Safont MJ, Ferreiro R, Rivera F, González E, Valladares-Ayerbes M, Grávalos C, Alonso-Orduña V, Viéitez JM, Yubero A, Aranda E. First-Line Biological Agents Plus Chemotherapy in Older Patients with Metastatic Colorectal Cancer: A Retrospective Pooled Analysis. Drugs Aging 2021; 38:219-231. [PMID: 33615402 PMCID: PMC7914239 DOI: 10.1007/s40266-021-00834-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/07/2021] [Indexed: 01/13/2023]
Abstract
BACKGROUND Biologicals, in combination with chemotherapy, are recommended as first-line treatment of metastatic colorectal cancer (mCRC); however, evidence guiding the appropriate management of older patients with mCRC is limited. OBJECTIVE This study was undertaken to compare the efficacy and safety outcomes in older versus younger patients with mCRC who received first-line biological therapy. METHODS This retrospective analysis used pooled data from five trials undertaken by the Spanish Cooperative Group for the Treatment of Digestive Tumours. All were studies of adults with advanced CRC who received first-line treatment with chemotherapy plus bevacizumab, cetuximab or panitumumab, stratified by age (≥ 65 vs. < 65 years). Endpoints included progression-free survival (PFS), overall survival (OS), overall response rate (ORR) and safety. RESULTS In total, 999 patients from five studies were included in the analysis: 480 (48%) were aged ≥ 65 years, and 519 (52%) were aged < 65 years. Median PFS did not differ significantly between patients aged ≥ 65 and < 65 years (9.9 vs. 9.4 months; hazard ratio [HR] 1.01; 95% confidence interval [CI] 0.88-1.17). Median OS was significantly shorter in older than in younger patients (21.3 vs. 25.0 months; HR 1.21; 95% CI 1.04-1.41). There was no significant difference between older and younger patients in ORR (59 vs. 62%). Patients aged ≥ 65 years experienced significantly more treatment-related grade 3 or higher adverse events (61.67%) than did patients aged < 65 years (45.86%). CONCLUSIONS Biologicals plus chemotherapy is an effective first-line treatment option for selected patients aged ≥ 65 years with mCRC and has a manageable safety profile and efficacy comparable to that observed in younger patients.
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Affiliation(s)
- Pilar García-Alfonso
- Servicio de Oncología, Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
| | - Eduardo Díaz-Rubio
- CIBERONC, Hospital Clínico San Carlos, Instituto de Investigación Hospital Clinico San Carlos (IdISSC), Madrid, Spain
| | - Albert Abad
- ICO, Hospital Germans Trias i Pujol, Badalona, Spain
- IOR Hospital Universitario Dexeus, Barcelona, Spain
| | - Alfredo Carrato
- IRYCIS, CIBERONC, Hospital Universitario Ramón y Cajal, Alcalá University, Madrid, Spain
| | | | - María José Ortiz-Morales
- IMIBIC, CIBERONC, Reina Sofía Hospital, Instituto de Salud Carlos III, University of Córdoba, Córdoba, Spain
| | | | - Andrés Muñoz
- Servicio de Oncología, Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Gema Durán
- Hospital Universitario Regional y Virgen de la Victoria, Malaga, Spain
| | - Javier Sastre
- CIBERONC, Hospital Clínico San Carlos, Instituto de Investigación Hospital Clinico San Carlos (IdISSC), Madrid, Spain
| | | | - Reyes Ferreiro
- IRYCIS, CIBERONC, Hospital Universitario Ramón y Cajal, Alcalá University, Madrid, Spain
| | - Fernando Rivera
- Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain
| | | | - Manuel Valladares-Ayerbes
- Instituto de Investigación Biomédica (INIBIC), Complejo Hospitalario Universitario A Coruña, A Coruña, Spain
| | | | - Vicente Alonso-Orduña
- Instituto de Investigación Sanitaria de Aragón (IISA), Hospital Universitario Miguel Servet, Zaragoza, Spain
| | | | - Alfonso Yubero
- Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain
| | - Enrique Aranda
- IMIBIC, CIBERONC, Reina Sofía Hospital, Instituto de Salud Carlos III, University of Córdoba, Córdoba, Spain
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16
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Dong M, Wang R, Sun P, Zhang D, Zhang Z, Zhang J, Tse G, Zhong L. Clinical significance of hypertension in patients with different types of cancer treated with antiangiogenic drugs. Oncol Lett 2021; 21:315. [PMID: 33692847 PMCID: PMC7933774 DOI: 10.3892/ol.2021.12576] [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: 08/23/2020] [Accepted: 01/13/2021] [Indexed: 12/13/2022] Open
Abstract
Hypertension is a common comorbidity in patients receiving antiangiogenic therapy. Prior studies have reported worsening or new-onset hypertension as an adverse event of antiangiogenetic therapy, which can be managed by dose reduction or discontinuation of the culprit medication. By contrast, other studies have found that the occurrence of hypertension is a potential biomarker associated with greater efficacy of antiangiogenic therapy and predicts improved survival. At present, there is no consensus on the effects of hypertension in patients treated with antiangiogenic drugs. The present study reviewed the relationship between antiangiogenic drugs and hypertension in different types of cancer. It was demonstrated that the use of antiangiogenic drugs was associated with an increased risk of hypertension in most types of solid cancers. There was no significant difference in the incidence of hypertension between monoclonal antibody and small-molecule tyrosine kinase inhibitor treatments. Hypertension was more likely to occur in patients younger than 75 years old, female, and those with no history of bevacizumab use. Discontinuation or death caused by hypertension was rare, although previous studies have reported that hypertension was a risk factor for acute and chronic cardiovascular diseases and ischemic stroke. Of note, the early development of hypertension may serve as a potential biomarker associated with greater efficacy of antiangiogenic therapy.
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Affiliation(s)
- Mei Dong
- Department of Cardiology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Rujian Wang
- Department of Oncology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Ping Sun
- Department of Oncology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Dongxia Zhang
- Department of Cardiology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Zhenzhen Zhang
- Department of Cardiology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Jing Zhang
- Department of Cardiology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Gary Tse
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China
| | - Lin Zhong
- Department of Cardiology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
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17
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Huang C, Gu X, Zeng X, Chen B, Yu W, Chen M. Cetuximab versus bevacizumab following prior FOLFOXIRI and bevacizumab in postmenopausal women with advanced KRAS and BRAF wild-type colorectal cancer: a retrospective study. BMC Cancer 2021; 21:30. [PMID: 33413175 PMCID: PMC7789412 DOI: 10.1186/s12885-020-07770-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 12/26/2020] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND An upgraded understanding of factors (sex/estrogen) associated with survival benefit in advanced colorectal carcinoma (CRC) could improve personalised management and provide innovative insights into anti-tumour mechanisms. The aim of this study was to assess the efficacy and safety of cetuximab (CET) versus bevacizumab (BEV) following prior 12 cycles of fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus BEV in postmenopausal women with advanced KRAS and BRAF wild-type (wt) CRC. METHODS Prospectively maintained databases were reviewed from 2013 to 2017 to assess postmenopausal women with advanced KRAS and BRAF wt CRC who received up to 12 cycles of FOLFOXIRI plus BEV inductive treatment, followed by CET or BEV maintenance treatment. The primary endpoints were overall survival (OS), progression-free survival (PFS), response rate. The secondary endpoint was the rate of adverse events (AEs). RESULTS At a median follow-up of 27.0 months (IQR 25.1-29.2), significant difference was detected in median OS (17.7 months [95% confidence interval [CI], 16.2-18.6] for CET vs. 11.7 months [95% CI, 10.4-12.8] for BEV; hazard ratio [HR], 0.63; 95% CI, 0.44-0.89; p=0.007); Median PFS was 10.7 months (95% CI, 9.8-11.3) for CET vs. 8.4 months (95% CI, 7.2-9.6) for BEV (HR, 0.67; 95% CI 0.47-0.94; p=0.02). Dose reduction due to intolerable AEs occurred in 29 cases (24 [24.0%] for CET vs. 5 [4.8%] for BEV; p< 0.001). CONCLUSIONS CET tends to be superior survival benefit when compared with BEV, with tolerated AEs.
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Affiliation(s)
- Chunlong Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan 2nd Road, Yuexiu District, Guangzhou, 510080 China
| | - Xiaoyuan Gu
- Department of Oncology, Shibei Hospital of Shanghai, No. 4500, Goughexin Road, Jing’ an District, Shanghai, 200443 China
| | - Xianshang Zeng
- Department of Orthopaedics, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan 2nd Road, Yuexiu District, Guangzhou, 510080 China
| | - Baomin Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan 2nd Road, Yuexiu District, Guangzhou, 510080 China
| | - Weiguang Yu
- Department of Orthopaedics, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan 2nd Road, Yuexiu District, Guangzhou, 510080 China
| | - Meiji Chen
- Department of Pediatrics, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan 2nd Road, Yuexiu District, Guangzhou, 510080 China
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18
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Tuca A, Gallego R, Ghanem I, Gil-Raga M, Feliu J. Chemotherapy and Targeted Agents in the Treatment of Elderly Patients with Metastatic Colorectal Cancer. J Clin Med 2020; 9:E4015. [PMID: 33322567 PMCID: PMC7764481 DOI: 10.3390/jcm9124015] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 12/04/2020] [Accepted: 12/07/2020] [Indexed: 12/20/2022] Open
Abstract
Colorectal cancer (CRC) is one of the main causes of cancer death in the elderly. The older patients constitute a heterogeneous group in terms of functional status, comorbidities, and aging-related conditions. Therefore, therapeutic decisions need to be individualized. Additionally, a higher toxicity risk comes from the fact that pharmacokinetics and pharmacodynamics of the drugs as well as the tissue tolerance can be altered with aging. Although the chemotherapy efficacy in metastatic colorectal cancer (mCRC) is similar for older and young patients, more toxicity is presented in the elderly. While the mono-chemotherapy provides the same benefit for young and older patients, doublets front-line chemotherapy improves progression-free survival (PFS) but not overall survival (OS) in the elderly. Furthermore, the benefit of the addition of bevacizumab to chemotherapy in older patients has been shown in several clinical trials, while the clinical data for the benefit of anti-epidermal growth factor antibodies are scarcer. Immunocheckpoint inhibitors could be an appropriate option for patients with microsatellite instability (MSI) tumors. A prior geriatric assessment is required before deciding the type of treatment in order to offer the best therapeutic option.
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Affiliation(s)
- Albert Tuca
- Department of Medical Oncology, Hospital Clinic, 08036 Barcelona, Spain;
| | - Rosa Gallego
- Department of Medical Oncology, General Hospital of Granollers, 08402 Granollers, Spain;
| | - Ismael Ghanem
- Department of Medical Oncology, Hospital Universitario La Paz, CIBERONC, 28046 Madrid, Spain;
| | - Mireia Gil-Raga
- Department of Medical Oncology, University General Hospital of Valencia, CIBERONC, 46014 Valencia, Spain;
| | - Jaime Feliu
- Department of Medical Oncology, Hospital Universitario La Paz, CIBERONC, 28046 Madrid, Spain;
- Cátedra UAM-AMGEN, 28049 Madrid, Spain
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19
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Ackland SP, Michael M, Souza P, Martin JH, Clarke SJ, Francis K, Karapetis CS, Gurney H. Science and art of
anticancer
drug dosing: nine steps to personalised therapy. Intern Med J 2020. [DOI: 10.1111/imj.14948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Affiliation(s)
- Stephen P. Ackland
- Faculty of Health and MedicineUniversity of Newcastle Newcastle New South Wales Australia
- Department of Medical OncologyCalvary Mater Newcastle Newcastle New South Wales Australia
- Hunter Medical Research Institute Newcastle New South Wales Australia
| | - Michael Michael
- Department of Medical OncologyPeter MacCallum Cancer Centre Melbourne Victoria Australia
| | - Paul Souza
- School of MedicineUniversity of Wollongong Wollongong New South Wales Australia
| | - Jennifer H. Martin
- Hunter Medical Research Institute Newcastle New South Wales Australia
- Centre for Human Drug Research, School of Medicine and Public Health, Faculty of Health and MedicineUniversity of Newcastle Newcastle New South Wales Australia
| | - Stephen J. Clarke
- Department of Medical OncologyRoyal North Shore Hospital Sydney New South Wales Australia
- Sydney Medical SchoolUniversity of Sydney Sydney New South Wales Australia
| | - Kay Francis
- Medical Oncology Group of Australia Sydney New South Wales Australia
| | - Christos S. Karapetis
- Medical Oncology Group of Australia Sydney New South Wales Australia
- Flinders Centre for Innovation in CancerFlinders University and Flinders Medical Centre Adelaide South Australia Australia
| | - Howard Gurney
- Crown Princess Mary Cancer CentreWestmead Hospital Sydney New South Wales Australia
- Faculty of Medicine and Health SciencesMacquarie University Sydney New South Wales Australia
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20
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Van Cutsem E, Danielewicz I, Saunders MP, Pfeiffer P, Argilés G, Borg C, Glynne-Jones R, Punt CJA, Van de Wouw AJ, Fedyanin M, Stroyakovskiy D, Kroening H, Garcia-Alfonso P, Wasan H, Falcone A, Kanehisa A, Egorov A, Aubel P, Amellal N, Moiseenko V. Trifluridine/tipiracil plus bevacizumab in patients with untreated metastatic colorectal cancer ineligible for intensive therapy: the randomized TASCO1 study. Ann Oncol 2020; 31:1160-1168. [PMID: 32497736 DOI: 10.1016/j.annonc.2020.05.024] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 05/20/2020] [Accepted: 05/22/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND We designed an open-label, noncomparative phase II study to assess the safety and efficacy of first-line treatment with trifluridine/tipiracil plus bevacizumab (TT-B) and capecitabine plus bevacizumab (C-B) in untreated patients with unresectable metastatic colorectal cancer (mCRC) who were not candidates for combination with cytotoxic chemotherapies. PATIENTS AND METHODS From 29 April 2016 to 29 March 2017, 153 patients were randomly assigned (1:1) to either TT-B (N = 77) or C-B (N = 76). The primary end point was progression-free survival (PFS). The primary PFS analysis was performed after 100 events (radiological progression or death) were observed. Secondary end points included overall survival (OS), quality of life (QoL; QLQ-C30 and QLQ-CR29 questionnaires), and safety. RESULTS Median (range) duration of treatment was 7.8 (6.0-9.7) months and 6.2 (4.1-9.1) months in the TT-B and C-B groups, respectively. Median (range) PFS was 9.2 (7.6-11.6) and 7.8 (5.5-10.1) months, respectively. Median (range) OS was 18 (15.2 to NA) and 16.2 (12.5 to NA) months, respectively. QoL questionnaires showed no relevant changes over time for either treatment. Therapies were well tolerated. Patients receiving TT-B had more grade ≥3 neutropenia (47% versus 5% with C-B). Patients receiving C-B had more grade ≥3 hand-foot syndrome (12% versus 0% with TT-B) and grade ≥3 diarrhea (8% versus 1% with TT-B), consistent with the known safety profiles of these agents. CONCLUSION TT-B treatment showed promising clinical activity in untreated patients with unresectable mCRC ineligible for intensive therapy, with an acceptable safety profile and no clinically relevant changes in QoL. CLINICAL TRIAL INFORMATION NCT02743221 (ClinicalTrials.gov).
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Affiliation(s)
- E Van Cutsem
- University Hospitals Leuven and KU Leuven, Leuven, Belgium.
| | - I Danielewicz
- Szpitale Wojewodzkie w Gdyni/Gdansk Medical University, Gdynia, Poland
| | - M P Saunders
- Christie Hospital NHS Foundation Trust, Manchester, UK
| | - P Pfeiffer
- Odense University Hospital, Odense, Denmark
| | - G Argilés
- Vall d'Hebrón Institute of Oncology and Vall d'Hebrón University Hospital, Barcelona, Spain
| | - C Borg
- University Hospital Besançon, Besançon, France
| | | | - C J A Punt
- Amsterdam University Medical Centers, Amsterdam
| | - A J Van de Wouw
- VieCuri Medisch Centrum Noord-Limburg, Venlo, The Netherlands
| | - M Fedyanin
- NN Blokhin National Medical Research Center of Oncology, Moscow, Russia
| | | | - H Kroening
- Schwerpunktpraxis für Haematologie und Onkologie Hasselbachplatz, Magdeburg, Germany
| | | | - H Wasan
- Hammersmith Hospital, Imperial College London, London, UK
| | - A Falcone
- University Hospital of Pisa, Department of Oncology, Pisa, Italy
| | - A Kanehisa
- Institut de Recherches Internationales Servier, Suresnes, France
| | - A Egorov
- Institut de Recherches Internationales Servier, Suresnes, France
| | - P Aubel
- Institut de Recherches Internationales Servier, Suresnes, France
| | - N Amellal
- Institut de Recherches Internationales Servier, Suresnes, France
| | - V Moiseenko
- Saint-Petersburg Scientific Practical Center for Specialized Medical Care, St Petersburg, Russia
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21
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Aparicio T, Canouï-Poitrine F, Caillet P, François E, Cudennec T, Carola E, Albrand G, Bouvier AM, Petri C, Couturier B, Phelip JM, Bengrine-Lefevre L, Paillaud E. Treatment guidelines of metastatic colorectal cancer in older patients from the French Society of Geriatric Oncology (SoFOG). Dig Liver Dis 2020; 52:493-505. [PMID: 32029404 DOI: 10.1016/j.dld.2019.12.145] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 12/21/2019] [Accepted: 12/23/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Several guidelines dedicated to metastatic colorectal cancer (mCRC) are available. Since 2013 no recent guidelines are specifically dedicated to older patients and based on a systematic review. MATERIALS AND METHODS A multidisciplinary Task Force with digestive oncologists, geriatricians and methodologists from the SoFOG was formed in 2016 to update recommendations on medical treatment of mCRC based on a systematic review of publications from 2000 to 2018. Search strategy has followed a standardized protocol from the formulation of clinical questions and definition of a search algorithm to the selection of complete articles for recommendations. RESULTS The four selected key questions were: For which older patients with mCRC can we considered: (1) Any chemotherapy, (2) Mono or poly-chemotherapy, (3) Anti-angiogenic therapy, (4) Other targeted therapy. Main recommendations for older patients are: (1) Omission of chemotherapy should be discussed with a geriatrician for patients with severe comorbidities, advanced dementia, uncontrolled psychiatric disorder or severe loss of autonomy. (2) If tumor response is not the main aim, a mono-chemotherapy with 5-fluorouracil combined with bevacizumab is recommended as first-line. (3) For patients with symptoms related to metastases or with a planned metastasis ablation, a doublet chemotherapy combined with bevacizumab or anti-EGFR antibody in the context of a RAS wild type tumor is recommended as first-line. Preliminary data suggest that regorafenib may be used, in its registered indication, in patients under 80 with a performance status of 0 and no autonomy alterations and that trifluridine-tipiracil may be used with a tight supervising of hematological function.
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Affiliation(s)
- Thomas Aparicio
- Department of Gastroenterology and Digestive Oncology, Saint Louis Hospital, AP-HP, University of Paris, Paris, France.
| | - Florence Canouï-Poitrine
- Clinical Epidemiology and Ageing Unit, Henri Mondor Hospital, APHP, EA 7376, CEpiA- IMRB, University of Paris-Est, Créteil, France
| | - Philippe Caillet
- Department of Geriatry, Georges Pompidou Hospital, APHP, University of Paris, Paris, France
| | - Eric François
- Department of Medical Oncology, Antoine-Lacassagne Center, University Côte d'Azur, Nice, France
| | - Tristan Cudennec
- Department of Geriatry, Ambroise Paré Hospital, APHP, University Versailles - Saint Quentin, Boulogne-Billancourt, France
| | - Elisabeth Carola
- Department of Medical Oncology, Public Sud de l'Oise Hospital, Creil, France
| | - Gilles Albrand
- Department of Geriatry, Lyon-Sud Hospital, Hospices Civils de Lyon, Pierre Bénite, France
| | - Anne-Marie Bouvier
- Digestive Cancer Registry of Burgundy, INSERM UMR1231 EPICAD University of Burgundy Franche Comté, Dijon, France
| | - Camille Petri
- Clinical Epidemiology and Ageing Unit, Henri Mondor Hospital, APHP, EA 7376, CEpiA- IMRB, University of Paris-Est, Créteil, France
| | - Bérengère Couturier
- Clinical Epidemiology and Ageing Unit, Henri Mondor Hospital, APHP, EA 7376, CEpiA- IMRB, University of Paris-Est, Créteil, France
| | - Jean-Marc Phelip
- Department of Gastroenterology and Digestive Oncology, Saint-Etienne Hospital, University Jean Monnet, Saint-Priest-en-Jarez, France
| | | | - Elena Paillaud
- Department of Geriatry, Georges Pompidou Hospital, APHP, University of Paris, Paris, France
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22
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Pharmacokinetics of mitomycin-c lipidic prodrug entrapped in liposomes and clinical correlations in metastatic colorectal cancer patients. Invest New Drugs 2020; 38:1411-1420. [DOI: 10.1007/s10637-020-00897-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 01/10/2020] [Indexed: 11/25/2022]
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23
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Moriwaki T, Sakai Y, Ishida H, Yamamoto Y, Endo S, Kuramochi H, Sato M, Hatachi Y, Bando Y, Maeba T, Ikezawa K, Shimada M, Amagai K, Morimoto M, Kobayashi K, Tsuji A, Nishina T, Hyodo I. Phase II study of S-1 on alternate days plus bevacizumab in patients aged ≥ 75 years with metastatic colorectal cancer (J-SAVER). Int J Clin Oncol 2019; 24:1214-1222. [PMID: 31089842 DOI: 10.1007/s10147-019-01465-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 05/04/2019] [Indexed: 11/24/2022]
Abstract
BACKGROUND Alternate-day administration of S-1 is thought to reduce toxicities. This phase II study evaluated S-1 on alternate days combined with bevacizumab as first-line treatment for elderly patients with metastatic colorectal cancer. PATIENTS AND METHODS Eligible patients had histologically proven colorectal adenocarcinoma, measurable metastatic lesions, age ≥ 75 years, Eastern Cooperative Oncology Group performance status ≤ 1, no previous chemotherapy, and refused oxaliplatin- or irinotecan-containing regimens. Patients received 40 mg, 50 mg, or 60 mg (body surface area ≤ 1.25 m2, > 1.25 to ≤ 1.50 m2, or > 1.50 m2, respectively) of S-1 twice orally on Sunday, Monday, Wednesday, and Friday every week. Bevacizumab (7.5 mg/kg) was administered every 3 weeks. The primary endpoint was progression-free survival. RESULTS Of 54 enrolled patients, 50 patients were evaluated for efficacy and 53 for safety. The median age was 79 years (range 75-88 years). The median progression-free survival was 8.1 months (95% confidence interval (CI) 6.7-9.5 months). The median overall survival was 23.1 months (95% CI 17.4-28.8 months). The response rate was 44% (95% CI 30.2-57.8%), and the disease control rate was 88% (95% CI 79.0-97.0%). Grade 3 or higher hematologic, non-hematologic, and bevacizumab-related adverse events occurred in 9%, 11%, and 25% of patients, respectively. The most common grade 3 and 4 treatment-related adverse events were hypertension (11%), nausea (6%), fatigue (6%), anemia (6%), and proteinuria (6%). Only 6 patients discontinued treatment due to adverse events. CONCLUSION S-1 on alternate days combined with bevacizumab showed better tolerability and comparable survival compared with the results of similar studies.
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Affiliation(s)
- Toshikazu Moriwaki
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, 305-8575, Ibaraki, Japan.
| | - Yoshinori Sakai
- Department of Gastroenterology, Tsuchiura Kyodo General Hospital, Tsuchiura City, Ibaraki, Japan
| | - Hiroyasu Ishida
- Department of Gastroenterology, National Hospital Organization Mito Medical Center, Higashi Ibaraki-Gun, Ibaraki, Japan
| | - Yoshiyuki Yamamoto
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, 305-8575, Ibaraki, Japan
| | - Shinji Endo
- Division of Gastroenterology and Hepatology, Shinmatsudo Central General Hospital, Matsudo City, Chiba, Japan
| | - Hideaki Kuramochi
- Department of Chemotherapy, Yachiyo Medical Center, Tokyo Women's University, Yachiyo City, Chiba, Japan
| | - Mikio Sato
- Department of Gastroenterology and Hepatology, Ryugasaki Saiseikai Hospital, Ryugasaki City, Ibaraki, Japan
| | - Yukimasa Hatachi
- Department of Medical Oncology, Kobe City Medical Center General Hospital, Kobe City, Hyogo, Japan
| | - Yoshiaki Bando
- Department of Surgery, Tokushima Prefecture Naruto Hospital, Naruto City, Tokushima, Japan
| | - Takashi Maeba
- Department of Surgery, Japan Community Health Care Organization Ritsurin Hospital, Takamatsu City, Kagawa, Japan
| | - Kazuto Ikezawa
- Division of Gastroenterology, Department of Internal Medicine, Tsukuba Memorial Hospital, Tsukuba City, Ibaraki, Japan
| | - Mitsuo Shimada
- Department of Surgery, Tokushima University, Tokushima City, Tokushima, Japan
| | - Kenji Amagai
- Division of Gastroenterology and G.I. Oncology, Ibaraki Prefectural Central Hospital and Cancer Center, Kasama City, Ibaraki, Japan
| | | | - Kazuma Kobayashi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki City, Nagasaki, Japan
| | - Akihito Tsuji
- Department of Clinical Oncology, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa, Japan
| | - Tomohiro Nishina
- Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama City, Ehime, Japan
| | - Ichinosuke Hyodo
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, 305-8575, Ibaraki, Japan
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24
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Aparicio T, Bouché O, Taieb J, Maillard E, Kirscher S, Etienne PL, Faroux R, Khemissa Akouz F, El Hajbi F, Locher C, Rinaldi Y, Lecomte T, Lavau-Denes S, Baconnier M, Oden-Gangloff A, Genet D, Paillaud E, Retornaz F, François E, Bedenne L. Bevacizumab+chemotherapy versus chemotherapy alone in elderly patients with untreated metastatic colorectal cancer: a randomized phase II trial-PRODIGE 20 study results. Ann Oncol 2019; 29:133-138. [PMID: 29045659 PMCID: PMC5834151 DOI: 10.1093/annonc/mdx529] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Background Metastatic colorectal cancer frequently occurs in elderly patients. Bevacizumab in combination with front line chemotherapy (CT) is a standard treatment but some concern raised about tolerance of bevacizumab for these patients. The purpose of PRODIGE 20 was to evaluate tolerance and efficacy of bevacizumab according to specific end points in this population. Patients and methods Patients aged 75 years and over were randomly assigned to bevacizumab + CT (BEV) versus CT. LV5FU2, FOLFOX and FOLFIRI regimen were prescribed according to investigator’s choice. The composite co-primary end point, assessed 4 months after randomization, was based on efficacy (tumor control and absence of decrease of the Spitzer QoL index) and safety (absence of severe cardiovascular toxicities and unexpected hospitalization). For each arm, the treatment will be consider as inefficient if 20% or less of the patients met the efficacy criteria and not safe if 40% or less met the safety criteria. Results About 102 patients were randomized (51 BEV and 51 CT), median age was 80 years (range 75–91). Primary end point was met for efficacy in 50% and 58% and for safety in 61% and 71% of patients in BEV and CT, respectively. Median progression-free survival was 9.7 months in BEV and 7.8 months in CT. Median overall survival was 21.7 months in BEV and 19.8 months in CT. The 36-month overall survival rate was 27% in BEV and 10.1% in CT. Severe toxicities grade 3/4 were mainly non-hematologic toxicities (80.4% in BEV, 63.3% in CT). Conclusion Bevacizumab combined with CT was safe and efficient. Both arms met the primary safety and efficacy criteria.
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Affiliation(s)
- T Aparicio
- Gastroenterology Department, CHU Saint Louis, APHP, Paris, France.,Université Paris 7, Sorbonne Paris Cité, Paris, France
| | - O Bouché
- Digestive Oncology Department, CHU Robert Debré, Reims, France
| | - J Taieb
- Digestive Oncology Department, CHU Georges Pompidou, APHP, Paris, France
| | - E Maillard
- Statistics Department, Fédération Francophone de Cancérologie Digestive, Dijon, France
| | - S Kirscher
- Oncology Department, Institut Sainte Catherine, Avignon, France
| | - P-L Etienne
- Oncology Department, CARIO, HPCA, Plérin, France
| | - R Faroux
- Gastroenterology Department, CHG Vendée, La Roche sur Yon, France
| | | | - F El Hajbi
- Oncology Department, Centre Oscar Lambret, Lille, France
| | - C Locher
- Gastroenterology Department, CH Meaux, Meaux, France
| | - Y Rinaldi
- Gastroenterology Departement, Hôpital Européen, Marseille, France
| | - T Lecomte
- Gastroenterology Department, CHU Trousseau, Tours, France
| | | | - M Baconnier
- Gastroenterology Department, CH Annecy Genevois, Pringy, France
| | - A Oden-Gangloff
- Gastroenterology Department, CHU Charles Nicolle, Rouen, France
| | - D Genet
- Oncology Department, Clinique Chenieux, Limoges, France
| | - E Paillaud
- Geriatric Department, CHU Henri Mondor, APHP, Créteil, France
| | - F Retornaz
- Geriatric Department, Hôpital Européen, Marseille, France
| | - E François
- Gastroenterology Department, Centre Antoine Lacassagne, Nice, France
| | - L Bedenne
- Gastroenterology Department, CHU Le Bocage, INSERM U 866, Dijon, France
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Modest DP, Pant S, Sartore-Bianchi A. Treatment sequencing in metastatic colorectal cancer. Eur J Cancer 2019; 109:70-83. [PMID: 30690295 DOI: 10.1016/j.ejca.2018.12.019] [Citation(s) in RCA: 227] [Impact Index Per Article: 37.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2018] [Accepted: 12/18/2018] [Indexed: 12/17/2022]
Abstract
Metastatic colorectal cancer (mCRC) remains incurable in most cases, but survival has improved with advances in cytotoxic chemotherapy and targeted agents. However, the optimal use and sequencing of these agents across multiple lines of treatment is unclear. Here, we review current treatment approaches and optimal treatment sequencing across the first-, second- and third-line settings in mCRC, including biological aspects affecting sequencing and rechallenge. Effective first-line therapy is a key determinant of treatment outcomes and should be selected after considering both clinical factors and biological markers, notably RAS and BRAF. The second-line regimen choice depends on the systemic therapies given in first-line. Anti-angiogenic agents (e.g. bevacizumab, ramucirumab and aflibercept) are indicated for most patients, whereas epidermal growth factor receptor (EGFR) inhibitors do not improve survival in the second-line setting. Molecular profiling is important in third-line treatment, with options in RAS wild-type patients including EGFR inhibitors (cetuximab or panitumumab), regorafenib and trifluridine/tipiracil. Immunotherapy with pembrolizumab or nivolumab ± ipilimumab may be considered for patients with high microsatellite instability disease. Targeting HER2/neu amplification shows promise for the subset of CRC tumours displaying this abnormality. Sequencing decisions are complicated by the potential for any treatment break or de-escalation to evoke a distinct clinical progression type. Ongoing trials are investigating the optimal sequencing and timing of therapies for mCRC. Molecular profiling has established new targets, and increasing knowledge of tumour evolution under drug pressure will possibly impact on sequencing.
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Affiliation(s)
- D P Modest
- Department of Medicine III, University Hospital, LMU Munich, Germany.
| | - S Pant
- Department of Investigational Cancer Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
| | - A Sartore-Bianchi
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Piazza Ospedale Maggiore, 3, 20162, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milano, Milan, Italy
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26
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Gómez-España MA, Gallego J, González-Flores E, Maurel J, Páez D, Sastre J, Aparicio J, Benavides M, Feliu J, Vera R. SEOM clinical guidelines for diagnosis and treatment of metastatic colorectal cancer (2018). Clin Transl Oncol 2018; 21:46-54. [PMID: 30565083 PMCID: PMC6339676 DOI: 10.1007/s12094-018-02002-w] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Accepted: 11/28/2018] [Indexed: 12/22/2022]
Abstract
Colorectal cancer (CRC) is the second cause of cancer death in Spain, the objective of this guide published by the Spanish Society of Medical Oncology is to develop a consensus for the diagnosis and management of metastatic disease. The optimal treatment strategy for patients with metastatic CRC should be discussed in a multidisciplinary expert team to select the most appropriate treatment, and integrate systemic treatment and other options such as surgery and ablative techniques depending on the characteristics of the tumour, the patient and the location of the disease and metastases.
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Affiliation(s)
- M A Gómez-España
- Servicio de Oncología Médica, H. Universitario Reina Sofía, IMIBIC, CIBERONC, Av. Menéndez Pidal, s/n, 14004, Córdoba, Spain.
| | - J Gallego
- Servicio de Oncología Médica, Hospital General Universitario, Elche, Spain
| | - E González-Flores
- Servicio de Oncología Médica, H. U. Virgen de las Nieves, Granada, Spain
| | - J Maurel
- Servicio de Oncología Médica, Hospital Clinic, Barcelona, Spain
| | - D Páez
- Servicio de Oncología Médica, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - J Sastre
- Servicio de Oncología Médica, Hospital Clínico San Carlos, IdISSC, CIBERONC, Madrid, Spain
| | - J Aparicio
- Servicio de Oncología Médica, Hospital Universitari i Politècnic La Fe, Valencia, Spain
| | - M Benavides
- Servicio de Oncología Médica, H.U. Regional y Virgen de la Victoria, Málaga, Spain
| | - J Feliu
- Servicio de Oncología Médica, H. U. La Paz, UAM, CIBERONC, Madrid, Spain
| | - R Vera
- Servicio de Oncología Médica, Complejo Hospitalario de Navarra, IdiSNA, Pamplona, Spain
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27
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Pfeiffer P, Köhne CH, Qvortrup C. The changing face of treatment for metastatic colorectal cancer. Expert Rev Anticancer Ther 2018; 19:61-70. [PMID: 30381969 DOI: 10.1080/14737140.2019.1543593] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Introduction: Since late 1990's therapy of metastatic colorectal cancer (mCRC) patients has changed considerable, and the combination of doublet or triplet chemotherapy and a targeted agent are now routinely used. With the introduction of more intensified regimens, it has become even more important to identify patients that will benefit from and can tolerate therapy. Furthermore, the increasing understanding of the biology of mCRC has led to the discovery of new potential targets. Therefore, therapy of patients with mCRC has undergone considerable change from 'one strategy fits all' towards a more personalized therapy. Areas covered: We present an overview of the recent literature on approved systemic treatment of mCRC however with focus on how the treatment strategy has changed based on clinical and molecular parameters that presently are used routinely in the clinical situation. Expert commentary: The face of treatment of mCRC has changed from 'one strategy fits all' to a personalized approach in which both clinical, molecular parameters and the aim of therapy have to be taking into account when planning the optimal treatment strategy for the individual mCRC patient.
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Affiliation(s)
- Per Pfeiffer
- a Department of Oncology , Odense University Hospital , Odense C , Denmark
| | - Claus-Henning Köhne
- b University Campus Klinikum Oldenburg, Carl von Ossietzky University, North-West-German Cancer Center , Oldenburg , NS , Germany
| | - Camilla Qvortrup
- c Department of Oncology, Rigshospitalet , Copenhagen University , Copenhagen , Denmark
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28
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Rocha LSDS, Riechelmann RP. Treatment of patients with metastatic colorectal cancer and poor performance status: current evidence and challenges. Clinics (Sao Paulo) 2018; 73:e542s. [PMID: 30281700 PMCID: PMC6142860 DOI: 10.6061/clinics/2018/e542s] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2017] [Accepted: 06/02/2018] [Indexed: 12/18/2022] Open
Abstract
Patients with unresectable metastatic colorectal cancer live for a median of three years when treated with standard therapies. While the evidence guiding cancer-directed treatment of this disease comes from phase III trials that have mostly enrolled patients with good performance status, some patients present with poor clinical conditions. The best treatment for these patients remains to be determined. We performed a systematic review of the treatment outcomes of patients with metastatic colorectal cancer and poor performance status, defined as Eastern Cooperative Oncology Group performance status ≥2. Eligible articles were prospective or retrospective studies or case reports published in English, Portuguese or Spanish. We searched PubMed, EMBASE, LILACS and the Cochrane Library from onset until October 2017 using specific keywords for each search. We found a total of 18 publications, mostly case reports and retrospective studies (14 articles). One was an uncontrolled prospective trial, two were observational studies and one was an individual patient meta-analysis. Although some studies suggested benefits in terms of symptomatic response with standard chemotherapy, with good safety profiles when dose-reduced regimens were administered, a true survival gain could not be demonstrated. The scientific evidence for treating metastatic colorectal cancer patients with poor performance status is scarce, and more studies evaluating treatment for this population are necessary since this condition is not uncommon in clinical practice, particularly in the public healthcare system and developing countries and among destitute populations.
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Affiliation(s)
- Lucila Soares da Silva Rocha
- Departamento de Radiologia e Oncologia, Instituto do Cancer do Estado de Sao Paulo (ICESP), Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, BR
| | - Rachel P. Riechelmann
- Departamento de Oncologia – AC Camargo Cancer Center, Sao Paulo, BR
- Programa de Pós-Graduação em Oncologia, Faculdade de Medicina da Universidade de Sao Paulo, São Paulo, BR
- *Corresponding author. E-mail:
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29
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Gouverneur A, Claraz P, Rousset M, Arnaud M, Fourrier-Réglat A, Pariente A, Aparicio T, Miremont-Salamé G, Noize P. Comparative Safety of Targeted Therapies for Metastatic Colorectal Cancer between Elderly and Younger Patients: a Study Using the International Pharmacovigilance Database. Target Oncol 2018; 12:805-814. [PMID: 29022151 DOI: 10.1007/s11523-017-0529-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Metastatic colorectal cancer (mCRC) is increasingly treated using targeted therapies. Post-marketing safety of these agents is understudied, especially in the elderly. OBJECTIVE This study aimed to compare, according to age, the adverse drug reactions (ADRs) of targeted therapies used for mCRC in real life. PATIENTS AND METHODS An extraction of VigiBase, which contains World Health Organization individual case safety reports (ICSRs), was performed. All ADR reports with aflibercept, bevacizumab, cetuximab, panitumumab, or regorafenib used in CRC were considered. For all drugs, chi-square tests were used to compare frequencies of serious ADRs between patients aged ≥75 and <75 years. For selected ADRs and each drug, the drug-ADR association compared to other anticancer drugs was estimated through the proportional reporting ratio (PRR) in both age groups. RESULTS There were 21,565 ICSRs included, among which 74% were serious and 11% were fatal. Median age was 64 years (Inter Quartile Range = 56-71) and 15% of patients were aged ≥75; 57% were male. Serious ICSRs accounted for 47,292 ADRs. Neutropenia was not more reported in elderly for all drugs while diarrhea was more reported in elderly for panitumumab. Cardiac disorders were more reported in elderly patients, in particular heart failure, especially for bevacizumab, cetuximab, and regorafenib, as were respiratory, thoracic, and mediastinal disorders. Most of PRR were not different between the two groups, except encephalopathies, which were significantly associated with bevacizumab in the elderly only. CONCLUSIONS ADRs related to targeted therapies used for mCRC treatment were different across age groups; yet, not systematically more reported or worse in elderly patients. Selected elderly patients could, therefore, be treated with these targeted therapies.
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Affiliation(s)
- Amandine Gouverneur
- Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, Team, Pharmacoepidemiology, UMR 1219, F-33000, Bordeaux, France. .,Bordeaux PharmacoEpi, INSERM CIC1401, F-33000, Bordeaux, France. .,CHU de Bordeaux, Pôle de Santé Publique, Service de Pharmacologie Médicale, F-33000, Bordeaux, France.
| | - Pauline Claraz
- CHU de Bordeaux, Pôle de Santé Publique, Service de Pharmacologie Médicale, F-33000, Bordeaux, France
| | - Marine Rousset
- Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, Team, Pharmacoepidemiology, UMR 1219, F-33000, Bordeaux, France.,CHU de Bordeaux, Pôle de Santé Publique, Service de Pharmacologie Médicale, F-33000, Bordeaux, France
| | - Mickaël Arnaud
- Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, Team, Pharmacoepidemiology, UMR 1219, F-33000, Bordeaux, France
| | - Annie Fourrier-Réglat
- Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, Team, Pharmacoepidemiology, UMR 1219, F-33000, Bordeaux, France.,Bordeaux PharmacoEpi, INSERM CIC1401, F-33000, Bordeaux, France.,CHU de Bordeaux, Pôle de Santé Publique, Service de Pharmacologie Médicale, F-33000, Bordeaux, France
| | - Antoine Pariente
- Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, Team, Pharmacoepidemiology, UMR 1219, F-33000, Bordeaux, France.,Bordeaux PharmacoEpi, INSERM CIC1401, F-33000, Bordeaux, France.,CHU de Bordeaux, Pôle de Santé Publique, Service de Pharmacologie Médicale, F-33000, Bordeaux, France
| | - Thomas Aparicio
- Gastroenterology and Digestive Oncology Department, Saint Louis Hospital, APHP, F-75010, Paris, France
| | - Ghada Miremont-Salamé
- Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, Team, Pharmacoepidemiology, UMR 1219, F-33000, Bordeaux, France.,CHU de Bordeaux, Pôle de Santé Publique, Service de Pharmacologie Médicale, F-33000, Bordeaux, France
| | - Pernelle Noize
- Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, Team, Pharmacoepidemiology, UMR 1219, F-33000, Bordeaux, France.,Bordeaux PharmacoEpi, INSERM CIC1401, F-33000, Bordeaux, France.,CHU de Bordeaux, Pôle de Santé Publique, Service de Pharmacologie Médicale, F-33000, Bordeaux, France
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30
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Landre T, Maillard E, Taleb C, Ghebriou D, Guetz GD, Zelek L, Aparicio T. Impact of the addition of bevacizumab, oxaliplatin, or irinotecan to fluoropyrimidin in the first-line treatment of metastatic colorectal cancer in elderly patients. Int J Colorectal Dis 2018; 33:1125-1130. [PMID: 29680896 DOI: 10.1007/s00384-018-3053-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/09/2018] [Indexed: 02/04/2023]
Abstract
INTRODUCTION The clinical benefit of double-front-line therapy (including oxaliplatin or irinotecan or bevacizumab plus 5-fluorouracil (5FU) or capecitabine) compared to monotherapy (5FU or capecitabine) in elderly (> 70 years) patients with metastatic colorectal cancer (MCRC) is controversial. We performed a meta-analysis of published randomized studies. MATERIALS AND METHODS The selection of the studies was carried out using PubMed with the following keywords: "metastatic colorectal cancer," "elderly," "oxaliplatin," "irinotecan," "bevacizumab," "survival." The efficacy endpoints were overall survival (OS) and progression-free survival (PFS). Hazard ratios (HRs) with their 95% confidence intervals (CIs) were collected from the studies and pooled. By convention, an HR < 1 was a result in favor of biotherapy. RESULTS This meta-analysis (MA) included ten studies: three assessing irinotecan (FFCD 2001-02, CAIRO, and an already published MA by Folprecht), three assessing oxaliplatin (FOCUS2, FFCD 2000-05, and a published study by De Gramont), and four assessing bevacizumab (PRODIGE-20, AVEX, AGITG-MAX, and "AVF2192g" by Kabbinavar). Our MA included 1652 patients (62% of men). Concerning age, we chose a cut-off of 70 years or a cut-off of 75 years, corresponding to the available data for each study. The performance index (PS) was 0-1 for about 90% of patients, with the exception of FFCD 2001-02 and FOCUS2 which included 30% of patients with PS2. Overall, the addition of bevacizumab to fluoropyrimidin statistically improves both OS and PFS (HR = 0.78; CI 0.63-0.96 and HR = 0.55; CI 0.44-0.67, respectively). The addition of oxaliplatin did not statistically improve OS (= 0.99; CI 0.85-1.17) but improves PFS (HR = 0.81; CI 0.67-0.97) as well as the addition of irinotecan (HR = 1.01; CI 0.84-1.22 and HR = 0.82; CI 0.68-1.00, respectively). CONCLUSION In previously untreated elderly patients with MCRC, the addition of bevacizumab to fluoropyrimidin appears more effective in terms of OS or PFS than the addition of oxaliplatin or irinotecan.
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Affiliation(s)
- Thierry Landre
- Geriatric Oncology Coordination Unit - UCOG 93, APHP, René Muret Hospital, HUPSSD - Université Paris 13, Sevran, France. .,FRancilian Oncogeriatric Group (FROG), Argenteuil, France.
| | - Emilie Maillard
- Department of Biostatistics, Fédération Française de Cancérologie Digestive, Dijon, France
| | - Chérifa Taleb
- Geriatric Oncology Coordination Unit - UCOG 93, APHP, René Muret Hospital, HUPSSD - Université Paris 13, Sevran, France.,Oncology Department, APHP, Avicenne Hospital, HUPSSD - Université Paris 13, Bobigny, France
| | - Djamel Ghebriou
- FRancilian Oncogeriatric Group (FROG), Argenteuil, France.,Department of Oncology, APHP, Tenon Hospital, Paris, France
| | - Gaetan Des Guetz
- Oncology Department, APHP, Avicenne Hospital, HUPSSD - Université Paris 13, Bobigny, France
| | - Laurent Zelek
- Geriatric Oncology Coordination Unit - UCOG 93, APHP, René Muret Hospital, HUPSSD - Université Paris 13, Sevran, France.,Oncology Department, APHP, Avicenne Hospital, HUPSSD - Université Paris 13, Bobigny, France
| | - Thomas Aparicio
- Department of Biostatistics, Fédération Française de Cancérologie Digestive, Dijon, France.,Gastroenterology Department, CHU Saint Louis, APHP, Université Paris 7, Sorbonne Paris Cité, Paris, France
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31
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Aparicio T, Bouché O, Francois E, Retornaz F, Barbier E, Taieb J, Kirscher S, Etienne PL, Faroux R, Khemissa Akouz F, El Hajbi F, Locher C, Rinaldi Y, Lecomte T, Lavau-Denes S, Baconnier M, Oden-Gangloff A, Genet D, Bedenne L, Paillaud E. Geriatric analysis from PRODIGE 20 randomized phase II trial evaluating bevacizumab + chemotherapy versus chemotherapy alone in older patients with untreated metastatic colorectal cancer. Eur J Cancer 2018; 97:16-24. [PMID: 29777975 DOI: 10.1016/j.ejca.2018.03.030] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2017] [Revised: 03/19/2018] [Accepted: 03/27/2018] [Indexed: 12/27/2022]
Abstract
BACKGROUND Older patients have frailty characteristics that impair the transposition of treatment results found in younger patients. Predictive factors are needed to help with treatment choices for older patients. The PRODIGE 20 study is a randomized phase II study that evaluated chemotherapy associated with bevacizumab (BEV) or not (CT) in patients aged 75 years or older. PATIENTS AND METHODS Patients underwent a geriatric assessment at randomization and at each evaluation. The predictive value of geriatric and oncologic factors was determined for the primary composite end-point assessing safety and efficacy of treatment (BEV or CT) simultaneously and also progression-free survival (PFS) and overall survival (OS). RESULTS 102 patients were randomized (51 BEV and 51 CT; median age 80 years [range 75-91]). On multivariate analysis, baseline normal independent activity of daily living (IADL) score and no previous cardiovascular disease predicted the primary end-point. High (versus low) baseline Köhne score predicted short PFS and baseline Spitzer quality of life (QoL) score <8, albumin level ≤35 g/L, CA19.9 >2 LN levels above normal and high baseline Köhne score predicted short OS. Survival without deteriorated QoL and autonomy was similar with BEV and CT. On subgroup analyses, the benefit of bevacizumab seemed to be maintained in patients with baseline impaired IADL or nutritional status. CONCLUSION Normal IADL score was associated with a good efficacy and safety of both BEV and CT. Köhne criteria may be relevant prognostic factors in older patients. Adding bevacizumab to chemotherapy does not impair patient autonomy or QoL.
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Affiliation(s)
- T Aparicio
- Gastroenterology Department, CHU Saint Louis, APHP and Université Paris 7, Sorbonne Paris Cité, Paris, France.
| | - O Bouché
- Digestive Oncology Department, CHU Robert Debré, Reims, France
| | - E Francois
- Gastroenterology Department, Centre Antoine Lacassagne, Nice, France
| | - F Retornaz
- Geriatric Department, Hôpital Européen, Marseille, France
| | - E Barbier
- Statistics Department, Fédération Francophone de Cancérologie Digestive, Dijon, France
| | - J Taieb
- Digestive Oncology Department, CHU Georges Pompidou, APHP, Paris, France
| | - S Kirscher
- Oncology Department, Institut Sainte Catherine, Avignon, France
| | - P-L Etienne
- Oncology Department, CARIO, HPCA, Plérin, France
| | - R Faroux
- Gastroenterology Department, CHG Vendée, La Roche sur Yon, France
| | | | - F El Hajbi
- Oncology Department, Centre Oscar Lambret, Lille, France
| | - C Locher
- Gastroenterology Department, CH Meaux, Meaux, France
| | - Y Rinaldi
- Gastroenterology Department, Hôpital Européen, Marseille, France
| | - T Lecomte
- Gastroenterology Department, CHU Trousseau, Tours, France
| | | | - M Baconnier
- Gastroenterology Department, CH Annecy Genevois, Pringy, France
| | - A Oden-Gangloff
- Gastroenterology Department, CHU Charles Nicolle, Rouen, France
| | - D Genet
- Oncology Department, Clinique Chenieux, Limoges, France
| | - L Bedenne
- Gastroenterology Department, CHU Le Bocage, INSERM U 866, Dijon, France
| | - E Paillaud
- Geriatric Department, CHU Henri Mondor, APHP, Créteil, France
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32
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Breadner D, Vincent MD, Jonker D, Cripps C, Klimo P, Biagi J, Lam W, O'Connell A, Whiston F, Stitt L, Welch S. Health related quality of life in older or frail patients with advanced colorectal cancer treated with dose reduced capecitabine. J Geriatr Oncol 2018; 9:659-664. [PMID: 29728308 DOI: 10.1016/j.jgo.2018.04.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Revised: 03/02/2018] [Accepted: 04/05/2018] [Indexed: 11/25/2022]
Abstract
OBJECTIVES Palliative chemotherapy's role is to prolong survival while minimizing treatment toxicities to preserve or improve quality of life. We have recently published a phase II trial of dose reduced capecitabine in older or frail patients with advanced colorectal cancer (aCRC). We herein provide a robust analysis of the health related quality of life (HRQoL) data from our trial. METHODS A single arm multi-centered phase II trial of dose reduced capecitabine (1500 or 2000 mg/m2 days one-fourteen q21 days) in older or frail patients. Participants (182 patients) were asked to complete Functional Assessment of Cancer Therapy general questionnaire (FACT-G) at enrollment, after each cycle of capecitabine, and once upon completion, if possible. RESULTS 157 patients completed a baseline questionnaire (86%), and 137 patients (75%) completed at least one subsequent questionnaire. The mean baseline score was 81.6, out of a possible 108. The mean score peaked at 92 after cycle 10. The mean change from baseline was always positive. Patients achieving the minimal clinically important difference (MCID) ranged from 30% to 45% during treatment. Higher baseline FACT-G and Physical Well-being score were independently prognostic for improved survival (p = 0.006 and p < 0.0001, respectively). Time until definitive deterioration (TUDD) was insignificantly longer in patients with a higher baseline FACT-G (p = 0.18). CONCLUSION Baseline HRQoL scores were independently prognostic for survival, supporting their importance. Compared to full dose, reduced dose capecitabine has previously demonstrated equivalent efficacy and reduced toxicity. We have reported dose reduced capecitabine improves quality of life in older or frail patients with aCRC, further supporting its use in the management of aCRC.
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Affiliation(s)
- Daniel Breadner
- London Regional Cancer Program, London, Ontario, Canada; Schulich School of Medicine and Dentistry, London, Ontario, Canada.
| | - Mark David Vincent
- London Regional Cancer Program, London, Ontario, Canada; Schulich School of Medicine and Dentistry, London, Ontario, Canada
| | - Derek Jonker
- Department of Medical Oncology, The Ottawa Hospital Cancer Centre, Ottawa, Ontario, Canada
| | - Christine Cripps
- Department of Medical Oncology, The Ottawa Hospital Cancer Centre, Ottawa, Ontario, Canada
| | - Paul Klimo
- Medical Oncology, Lions Gate Hospital, North Vancouver, British Columbia, Canada
| | - James Biagi
- Department of Oncology, Queen's University, Kingston, Ontario, Canada
| | - Wendy Lam
- Burnaby Hospital Cancer Centre, Burnaby, British Columbia, Canada
| | | | | | - Larry Stitt
- London Regional Cancer Program, London, Ontario, Canada
| | - Stephen Welch
- London Regional Cancer Program, London, Ontario, Canada; Schulich School of Medicine and Dentistry, London, Ontario, Canada
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33
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Apelin: A putative novel predictive biomarker for bevacizumab response in colorectal cancer. Oncotarget 2018; 8:42949-42961. [PMID: 28487489 PMCID: PMC5522118 DOI: 10.18632/oncotarget.17306] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Accepted: 04/04/2017] [Indexed: 12/17/2022] Open
Abstract
Bevacizumab (bvz) is currently employed as an anti-angiogenic therapy across several cancer indications. Bvz response heterogeneity has been well documented, with only 10-15% of colorectal cancer (CRC) patients benefitting in general. For other patients, clinical efficacy is limited and side effects are significant. This reinforces the need for a robust predictive biomarker of response. To identify such a biomarker, we performed a DNA microarray-based transcriptional profiling screen with primary endothelial cells (ECs) isolated from normal and tumour colon tissues. Thirteen separate populations of tumour-associated ECs and 10 of normal ECs were isolated using fluorescence-activated cell sorting. We hypothesised that VEGF-induced genes were overexpressed in tumour ECs; these genes could relate to bvz response and serve as potential predictive biomarkers. Transcriptional profiling revealed a total of 2,610 differentially expressed genes when tumour and normal ECs were compared. To explore their relation to bvz response, the mRNA expression levels of top-ranked genes were examined using quantitative PCR in 30 independent tumour tissues from CRC patients that received bvz in the adjuvant setting. These analyses revealed that the expression of MMP12 and APLN mRNA was significantly higher in bvz non-responders compared to responders. At the protein level, high APLN expression was correlated with poor progression-free survival in bvz-treated patients. Thus, high APLN expression may represent a novel predictive biomarker for bvz unresponsiveness.
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34
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McCleary NJ, Hubbard J, Mahoney MR, Meyerhardt JA, Sargent D, Venook A, Grothey A. Challenges of conducting a prospective clinical trial for older patients: Lessons learned from NCCTG N0949 (alliance). J Geriatr Oncol 2018; 9:24-31. [PMID: 28917648 PMCID: PMC5757827 DOI: 10.1016/j.jgo.2017.08.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Revised: 07/14/2017] [Accepted: 08/14/2017] [Indexed: 12/16/2022]
Abstract
OBJECTIVES While the risk of developing colorectal cancer increases with age, there are limited prospective data regarding best treatment in the older adult population. We launched a phase III trial to evaluate difference in treatment outcome for older adults (aged ≥70years) with advanced colorectal cancer. Here we review the challenges faced and reasons for poor accrual to N0949. MATERIALS AND METHODS We describe the conceptualization, development and limited results of N0949, a randomized phase III study of fluoropyrimidine/bevacizumab with or without oxaliplatin (mFOLFOX7 or XELOX) as first line chemotherapy for metastatic colorectal cancer. Fluoropyrimidine was physician choice (e.g., 5-FU/LV or capecitabine). RESULTS Of the projected 380 patients, only 32 patients were enrolled between the study activation in January 2011 until its closure in September 2012. Reasons for poor accrual included eligibility criteria that were too stringent, discomfort with randomizing older patients to regimens of varying intensity without considering their physical fitness, and discomfort with the use of bevacizumab in the older patient population. Several efforts were mounted to design a rationale and age-appropriate study, consider toxicities and varying study practices, and be responsive to stakeholder feedback. CONCLUSIONS Challenges were experienced in conducting the first prospective phase III study evaluating progression-free survival of older adults with advanced colorectal cancer receiving palliative chemotherapy with fluoropyrimidine/bevacizumab with or without oxaliplatin in the USA. Future efforts to evaluate treatment outcomes in the older adult population should reflect on lessons learned in this large national effort.
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Affiliation(s)
- Nadine J McCleary
- Department of Medical Oncology, Dana-Farber/Partners Cancer Care, Boston, MA, United States.
| | - Joleen Hubbard
- Department of Medical Oncology, Mayo Clinic, Rochester, MN, United States
| | - Michelle R Mahoney
- Alliance Statistics and Data Center, Mayo Clinic, Rochester, MN, United States
| | - Jeffrey A Meyerhardt
- Department of Medical Oncology, Dana-Farber/Partners Cancer Care, Boston, MA, United States
| | - Daniel Sargent
- Alliance Statistics and Data Center, Mayo Clinic, Rochester, MN, United States
| | - Alan Venook
- Department of Medical Oncology, University of San Francisco, CA, United States
| | - Axel Grothey
- Department of Medical Oncology, Mayo Clinic, Rochester, MN, United States
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Koch C, Schwing AM, Herrmann E, Borner M, Diaz-Rubio E, Dotan E, Feliu J, Okita N, Souglakos J, Arkenau HT, Porschen R, Koopman M, Punt CJA, de Gramont A, Tournigand C, Zeuzem S, Trojan J. Bevacizumab-based first-line chemotherapy in elderly patients with metastatic colorectal cancer: an individual patient data based meta-analysis. Oncotarget 2017. [PMID: 29535805 PMCID: PMC5828201 DOI: 10.18632/oncotarget.23475] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Background The aim of this meta-analysis was to evaluate efficacy and safety of first-line chemotherapy with or without a monoclonal antibody in elderly patients (≥ 70 years) with metastatic colorectal cancer (mCRC), since they are frequently underrepresented in clinical trials. Results Individual data from 10 studies were included. From a total of 3271 patients, 604 patients (18%) were ≥ 70 years (median 73 years, range 70-88). Of these, 335 patients were treated with a bevacizumab-based first-line regimen and 265 were treated with chemotherapy only. The median PFS was 8.2 vs. 6.5 months and the median OS was 16.7 vs. 13.0 months in patients treated with and without bevacizumab, respectively. The safety profile of bevacizumab in combination with first-line chemotherapy did not differ from published clinical trials. Materials and Methods PubMed and Cochrane Library searches were performed on 29 April 2013 and studies published to this date were included. Authors were contacted to request progression-free survival (PFS), overall survival (OS) data, patient data on treatment regimens, age, sex and potential signs of toxicity in patients ≥ 70 years of age. Conclusions This meta-analysis suggests that the addition of bevacizumab to standard first-line chemotherapy improves clinical outcome in elderly patients with mCRC and is well tolerated.
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Affiliation(s)
- Christine Koch
- Department of Gastroenterology, University Liver and Cancer Centre, Frankfurt, Germany
| | - Anna M Schwing
- Department of Gastroenterology, University Liver and Cancer Centre, Frankfurt, Germany
| | - Eva Herrmann
- Institute of Biostatistics and Mathematical Modelling, Johann Wolfgang Goethe-University, Frankfurt, Germany
| | - Markus Borner
- Medical Oncology Institute, Inselspital, Bern, Switzerland
| | | | - Efrat Dotan
- Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Jaime Feliu
- Department of Medical Oncology, La Paz University Hospital, CIBERONC, Madrid, Spain
| | | | - John Souglakos
- Department of Medical Oncology, University Hospital of Heraklion, University of Crete, Crete, Greece
| | | | | | - Miriam Koopman
- Department of Medical Oncology, University Medical Centre, Utrecht, The Netherlands
| | - Cornelis J A Punt
- Department of Medical Oncology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | | | | | - Stefan Zeuzem
- Department of Gastroenterology, University Liver and Cancer Centre, Frankfurt, Germany
| | - Joerg Trojan
- Department of Gastroenterology, University Liver and Cancer Centre, Frankfurt, Germany
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36
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Soto-Perez-de-Celis E, de Glas NA, Hsu T, Kanesvaran R, Steer C, Navarrete-Reyes AP, Battisti NML, Chavarri-Guerra Y, O’Donovan A, Avila-Funes JA, Hurria A. Global geriatric oncology: Achievements and challenges. J Geriatr Oncol 2017. [DOI: 10.1016/j.jgo.2017.06.001] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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Vincent MD, Breadner D, Cripps MC, Jonker DJ, Klimo P, Biagi JJ, Lam W, O'Connell A, Whiston F, Stitt L, Welch SA. Phase I/II trial of dose-reduced capecitabine in elderly patients with advanced colorectal cancer. ACTA ACUST UNITED AC 2017; 24:e261-e268. [PMID: 28874896 DOI: 10.3747/co.24.3516] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Combination chemotherapy is associated with improved outcomes in trials of selected fit patients with advanced colorectal cancer (acrc). For older or less-fit patients, combination chemotherapy is associated with greater toxicity and less benefit. Capecitabine monotherapy is a reasonable option for those patients, but the optimal dose remains controversial. METHODS A multicentre phase i/ii trial of reduced-dose capecitabine (2000 mg/m2, days 1-14 every 21 days) was conducted in 221 patients representing one or more of the following subsets: age greater than 65 years (n = 167), Eastern Cooperative Oncology Group (ecog) performance status of 1 or greater (n = 139), elevated lactate dehydrogenase (ldh) (n = 105), or prior pelvic radiation (n = 54). Based on phase i results, patients with prior pelvic radiation received capecitabine 750 mg/m2 twice daily. The goal was to ascertain efficacy in a design that was unlikely to cause high levels of toxicity. RESULTS Median age in the patient cohort was 72 years. A median of 5 and a mean of 8 capecitabine cycles were given (range: 0-50 cycles). Grade 3 or 4 toxicity occurred in 25% of patients during the first 3 cycles (8.1% hand-foot syndrome, 7.7% diarrhea). The response rate was 13.6%, with a 69.7% disease control rate. Median progression-free survival (pfs) was 5.6 months. Post progression, 56 patients received further capecitabine monotherapy (median of 4 additional cycles). Median overall survival duration for the patients was 14.3 months. Median survival was significantly higher for those who, at baseline, had an ecog performance status of 0 (compared with 1 or more) and normal ldh (compared with elevated ldh). CONCLUSIONS Toxicity is less with dose-reduced capecitabine than with historical full-dose capecitabine, with only a small trade-off in efficacy, seen as a lower objective response rate. The improved tolerability could lead to an increased number of cycles of therapy, and pfs appears to be consistently higher at the lower dose. Those observations should, in the absence of a head-to-head clinical trial, be viewed as compelling evidence that 1000 mg/m2, or even 750 mg/m2, twice daily is an appropriate dose in elderly or frail patients with acrc.
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Affiliation(s)
- M D Vincent
- London Regional Cancer Program, London, ON.,Schulich School of Medicine and Dentistry, London, ON
| | - D Breadner
- London Regional Cancer Program, London, ON.,Schulich School of Medicine and Dentistry, London, ON
| | - M C Cripps
- Department of Medical Oncology, The Ottawa Hospital Cancer Centre, Ottawa, ON
| | - D J Jonker
- Department of Medical Oncology, The Ottawa Hospital Cancer Centre, Ottawa, ON
| | - P Klimo
- Medical Oncology, Lions Gate Hospital, North Vancouver, BC
| | - J J Biagi
- Department of Oncology, Queen's University, Kingston, ON
| | - W Lam
- Burnaby Hospital Cancer Centre, Burnaby, BC
| | | | - F Whiston
- London Regional Cancer Program, London, ON
| | - L Stitt
- London Regional Cancer Program, London, ON
| | - S A Welch
- London Regional Cancer Program, London, ON.,Schulich School of Medicine and Dentistry, London, ON
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Gouverneur A, Salvo F, Berdaï D, Moore N, Fourrier-Réglat A, Noize P. Inclusion of elderly or frail patients in randomized controlled trials of targeted therapies for the treatment of metastatic colorectal cancer: A systematic review. J Geriatr Oncol 2017; 9:15-23. [PMID: 28844343 DOI: 10.1016/j.jgo.2017.08.001] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Revised: 06/23/2017] [Accepted: 08/09/2017] [Indexed: 01/20/2023]
Abstract
Treatment of metastatic colorectal cancer (mCRC) has been modified since the launching of targeted therapies. Colorectal cancer (CRC) is common in elderly patients; their representation in randomized controlled trials (RCTs) is thus crucial. This study aimed to evaluate and quantify the inclusion of elderly/frail patients in RCTs of targeted therapies in mCRC. A systematic review using Medline, Scopus, Cochrane Database and ISI Web of Science was performed to identify all phase II/III RCTs of bevacizumab, cetuximab, panitumumab, regorafenib and aflibercept in mCRC until January 2015. Two reviewers independently performed studies selection, and data extraction. The protocol was registered in Prospero (CRD42015016163). Among 1,369, identified publications, 54 RCTs were selected. Nine RCTs (17%) excluded elderly patients; median age of the included population was <65years old in 50 RCTs (93%). Twenty RCTs (37%) excluded frail patients, and many RCTs excluded patients with uncontrolled hypertension or heart failure, patients treated with specific drugs (mainly anticoagulants), and patients with inadequate creatinine clearance. Elderly/frail patients are underrepresented in RCTs studying targeted therapies in mCRC, and those elderly patients included in RCTs do not reflect well the general elderly population with mCRC because of the exclusion criteria. RCTs results concerning targeted therapies can be inferred only to relatively healthy elderly subjects.
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Affiliation(s)
- Amandine Gouverneur
- Univ. Bordeaux, INSERM, Bordeaux Population Health Research Center, Team Pharmacoepidemiology, UMR 1219, F-33000 Bordeaux, France; Bordeaux PharmacoEpi, INSERM CIC1401, F-33000 Bordeaux, France; CHU de Bordeaux, Pôle de santé publique, Service de Pharmacologie médicale, F-33000 Bordeaux, France.
| | - Francesco Salvo
- Univ. Bordeaux, INSERM, Bordeaux Population Health Research Center, Team Pharmacoepidemiology, UMR 1219, F-33000 Bordeaux, France; Bordeaux PharmacoEpi, INSERM CIC1401, F-33000 Bordeaux, France; CHU de Bordeaux, Pôle de santé publique, Service de Pharmacologie médicale, F-33000 Bordeaux, France
| | - Driss Berdaï
- CHU de Bordeaux, Pôle de santé publique, Service de Pharmacologie médicale, F-33000 Bordeaux, France
| | - Nicholas Moore
- Univ. Bordeaux, INSERM, Bordeaux Population Health Research Center, Team Pharmacoepidemiology, UMR 1219, F-33000 Bordeaux, France; Bordeaux PharmacoEpi, INSERM CIC1401, F-33000 Bordeaux, France; CHU de Bordeaux, Pôle de santé publique, Service de Pharmacologie médicale, F-33000 Bordeaux, France
| | - Annie Fourrier-Réglat
- Univ. Bordeaux, INSERM, Bordeaux Population Health Research Center, Team Pharmacoepidemiology, UMR 1219, F-33000 Bordeaux, France; Bordeaux PharmacoEpi, INSERM CIC1401, F-33000 Bordeaux, France; CHU de Bordeaux, Pôle de santé publique, Service de Pharmacologie médicale, F-33000 Bordeaux, France
| | - Pernelle Noize
- Univ. Bordeaux, INSERM, Bordeaux Population Health Research Center, Team Pharmacoepidemiology, UMR 1219, F-33000 Bordeaux, France; Bordeaux PharmacoEpi, INSERM CIC1401, F-33000 Bordeaux, France; CHU de Bordeaux, Pôle de santé publique, Service de Pharmacologie médicale, F-33000 Bordeaux, France
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Winther SB, Österlund P, Berglund Å, Glimelius B, Qvortrup C, Sorbye H, Pfeiffer P. Randomized study comparing full dose monotherapy (S-1 followed by irinotecan) and reduced dose combination therapy (S-1/oxaliplatin followed by S-1/irinotecan) as initial therapy for older patients with metastatic colorectal cancer: NORDIC 9. BMC Cancer 2017; 17:548. [PMID: 28814275 PMCID: PMC5559862 DOI: 10.1186/s12885-017-3526-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 08/01/2017] [Indexed: 12/22/2022] Open
Abstract
Background Metastatic colorectal cancer (mCRC) is a disease of older age, but there is a relative lack of knowledge about effects of chemotherapy in older patients as they are under-represented in clinical trials. Little data can guide whether the strategy in older mCRC patients should be a sequential full-dose monotherapy chemotherapy approach or a dose-reduced combination chemotherapy approach. The oral 5FU prodrug S-1 seems to have less side effects than capecitabine and should be an optimal drug for older patients, but few data are available. Improved geriatric assessments are needed to select which older patients should receive therapy. Methods The NORDIC 9 trial is a Nordic multicenter randomized phase II study comparing full dose monotherapy (S-1 30 mg/m2 twice daily days 1–14 every 3 weeks, followed by second line irinotecan 250–350 mg/m2 iv day 1 every 3 weeks or 180–250 mg/m2 iv day 1 every 2 weeks) with reduced dose combination therapy (S-1 20 mg/m2 days 1–14 + oxaliplatin 100 mg/m2 iv day 1 every 3 weeks, followed by second line S-1 20 mg/m2 days 1–14 + irinotecan 180 mg/m2 day 1 every 3 week) for older patients (≥70 years) with mCRC who are not candidates for full-dose standard combination therapy. Additional bevacizumab (7.5 mg/kg) is optional in first-line. Blood samples and tumor tissue will be collected to investigate predictive markers. Geriatric screening tools (G-8, VES-13, Timed-Up-and-Go and Handgrip strength), Charlson Comorbidty Index and quality of life (EORTC QLQ-C30) will be evaluated as predictors of efficacy and toxicity. The target sample size is 150 patients. The primary endpoint is progression-free survival and secondary endpoints are time-to-failure of strategy, overall survival, response rate, toxicity, and correlations between biomarkers, pre-treatment characteristics and geriatric assessments. Discussion The study will add knowledge on how to treat older mCRC patients who are not candidates for standard combination therapy. Furthermore it may provide understanding of efficacy and tolerability of chemotherapy in older cancer patients and thus offer a better chance for tailored treatment strategies in these patients. Trial registration EU Clinical Trial Register, EudraCT no. 2014–000394-39. Registered 05 May 2014.
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Affiliation(s)
| | - Pia Österlund
- Department of Oncology, Helsinki University Central Hospital, Stenbäckinkatu 9, PO BOX 100, FI-00029, Helsinki, Finland.,Clinicum, Helsinki University, Haartmaninkatu 8, 3th floor, PO BOX 63, 00014, Helsinki, Finland
| | - Åke Berglund
- Department of Immunology, Genetics and Pathology, Uppsala University, Dag Hammarskjölds väg 20, 751 85, Uppsala, Sweden
| | - Bengt Glimelius
- Department of Immunology, Genetics and Pathology, Uppsala University, Dag Hammarskjölds väg 20, 751 85, Uppsala, Sweden
| | - Camilla Qvortrup
- Department of Oncology, Odense University Hospital, Sdr. Boulevard 29, 5000, Odense C, Denmark
| | - Halfdan Sorbye
- Department of Oncology and Department of Clinical Science, Haukeland University Hospital, Postboks 1400, 5021, Bergen, Norway
| | - Per Pfeiffer
- Department of Oncology, Odense University Hospital, Sdr. Boulevard 29, 5000, Odense C, Denmark
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Targeted Therapies in Elderly Patients with Metastatic Colorectal Cancer: A Review of the Evidence. Drugs Aging 2017; 34:173-189. [PMID: 28197947 DOI: 10.1007/s40266-017-0439-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Metastatic colorectal cancer (mCRC) is the third leading cause of cancer deaths worldwide. As the population of the western world ages, the incidence of colorectal tumours among elderly patients is increasing and consequently so is the demand for treatments for elderly patients. Unfortunately, elderly patients (≥65 years) often go untreated and they are also under-represented in clinical trials. Yet there is some evidence suggesting that 'fit' elderly patients have similar outcomes and tolerance to chemotherapy treatment to their younger counterparts (although the definition of fitness in the elderly population is still a matter of debate). The evidence supporting the administration of new targeted therapies in patients older than 65 years is scarce and more research is needed. In this paper, we review all the available data concerning the use of targeted therapies for mCRC in patients older than 65 years of age and discuss the differences between this age subgroup and younger patients.
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41
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Zhao T, Wang X, Xu T, Xu X, Liu Z. Bevacizumab significantly increases the risks of hypertension and proteinuria in cancer patients: A systematic review and comprehensive meta-analysis. Oncotarget 2017; 8:51492-51506. [PMID: 28881662 PMCID: PMC5584263 DOI: 10.18632/oncotarget.18190] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Accepted: 02/20/2017] [Indexed: 01/18/2023] Open
Abstract
Published data regarding the overall risks and incidence of hypertension and proteinuria associated with bevacizumab were still unclear. To quantify the precise risks and incidence, we performed this comprehensive meta-analysis of 72 published clinical trials including 21902 cases and 20608 controls. The overall incidence, risk ratios (RRs), and 95% confidence intervals (95% CIs) were calculated using a fixed or random-effect model based on the heterogeneity. The incidence of all-grade and high-grade hypertension were 25.3% (95% CI: 21.5%−29.5%) and 8.2% (95% CI: 7%−9.8%) for patients treated with bevacizumab. And the incidence of all-grade and high-grade proteinuria were 18% (95% CI: 11.7%−26.6%) and 2.4% (95% CI: 1.8%−3.2%), respectively. Compared with controls, bevacizumab significantly increased the risks of all-grade (RR: 3.595, 95% CI: 2.952−4.378) and high-grade hypertension (RR: 5.173, 95% CI: 4.188−6.390). Obviously increased risks of all-grade (RR: 3.369, 95% CI: 2.492−4.556) and high-grade proteinuria (RR: 5.494, 95% CI: 3.991−7.564) were also observed. In the subgroup analysis, the risks of hypertension and proteinuria may significantly vary with bevacizumab dosage, cancer types and concomitant drugs. Whereas, no obvious difference were discovered when stratified based on phase of trials, age of patients, treatment line and duration. So, close monitor and effective management were highly recommended for the safe use of bevacizumab.
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Affiliation(s)
- Tingting Zhao
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu, 210002, China
| | - Xiaonan Wang
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu, 210002, China
| | - Tingting Xu
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu, 210002, China
| | - Xiaodong Xu
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu, 210002, China
| | - Zhihong Liu
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu, 210002, China
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Geriatric factors analyses from FFCD 2001-02 phase III study of first-line chemotherapy for elderly metastatic colorectal cancer patients. Eur J Cancer 2017; 74:98-108. [DOI: 10.1016/j.ejca.2016.09.029] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2016] [Revised: 09/20/2016] [Accepted: 09/23/2016] [Indexed: 01/29/2023]
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[Colorectal cancer in the elderly. Surgical treatment, chemotherapy, and contribution from geriatrics]. Rev Esp Geriatr Gerontol 2017; 52:261-270. [PMID: 28126268 DOI: 10.1016/j.regg.2016.10.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 10/14/2016] [Indexed: 12/12/2022]
Abstract
Age is the biggest risk factor for colorectal cancer, with 70% of the cases in patients over 70 years old. For this reason, a review is presented on the surgical treatment and chemotherapy of cancer of colon and rectum in the elderly. A search was performed in PubMed, including words such as elderly, surgery, colorectal cancer, chemotherapy, radiotherapy, and oncogeriatrics, and review articles and originals on treatment of colorectal cancer in the elderly were selected. A narrative form was developed from the latest evidence with the results obtained on the treatment of this pathology. Although the treatment of colorectal cancer is standardised, a prior comprehensive geriatric assessment is required in the case of the elderly, before deciding the type of treatment in order to offer these robust elderly-standardised guidelines for the robust elderly and adapt them for use in fragile patients.
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Sorio R, Roemer-Becuwe C, Hilpert F, Gibbs E, García Y, Kaern J, Huizing M, Witteveen P, Zagouri F, Coeffic D, Lück HJ, González-Martín A, Kristensen G, Levaché CB, Lee CK, Gebski V, Pujade-Lauraine E. Safety and efficacy of single-agent bevacizumab-containing therapy in elderly patients with platinum-resistant recurrent ovarian cancer: Subgroup analysis of the randomised phase III AURELIA trial. Gynecol Oncol 2017; 144:65-71. [DOI: 10.1016/j.ygyno.2016.11.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2016] [Revised: 11/02/2016] [Accepted: 11/04/2016] [Indexed: 10/20/2022]
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Moth EB, Vardy J, Blinman P. Decision-making in geriatric oncology: systemic treatment considerations for older adults with colon cancer. Expert Rev Gastroenterol Hepatol 2016; 10:1321-1340. [PMID: 27718755 DOI: 10.1080/17474124.2016.1244003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Colon cancer is common and can be considered a disease of older adults with more than half of cases diagnosed in patients aged over 70 years. Decision-making about treatment with chemotherapy for older adults may be complicated by age-related physiological changes, impaired functional status, limited social supports, concerns regarding the occurrence of and ability to tolerate treatment toxicity, and the presence of comorbidities. This is compounded by a lack of high quality evidence guiding cancer treatment decisions for older adults. Areas covered: This narrative review evaluates the evidence for adjuvant and palliative systemic therapy in older adults with colon cancer. The value of an adequate assessment prior to making a treatment decision is addressed, with emphasis on the geriatric assessment. Guidance in making a treatment decision is provided. Expert commentary: Treatment decisions should consider goals of care, a patient's treatment preferences, and weigh up relative benefits and harms.
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Affiliation(s)
- Erin B Moth
- a Concord Cancer Centre , Concord Repatriation General Hospital , Sydney , Australia.,b Sydney Medical School , University of Sydney , Sydney , Australia
| | - Janette Vardy
- a Concord Cancer Centre , Concord Repatriation General Hospital , Sydney , Australia.,b Sydney Medical School , University of Sydney , Sydney , Australia
| | - Prunella Blinman
- a Concord Cancer Centre , Concord Repatriation General Hospital , Sydney , Australia.,b Sydney Medical School , University of Sydney , Sydney , Australia
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Aparicio T, Pamoukdjian F, Quero L, Manfredi S, Wind P, Paillaud E. Colorectal cancer care in elderly patients: Unsolved issues. Dig Liver Dis 2016; 48:1112-8. [PMID: 27260332 DOI: 10.1016/j.dld.2016.05.011] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Revised: 04/24/2016] [Accepted: 05/12/2016] [Indexed: 12/11/2022]
Abstract
Colorectal cancers are common in elderly patients. However, cancer screening is poorly used after 75. Elderly patients form a heterogeneous population with specific characteristics. Standards of care cannot therefore be transposed from young to elderly patients. Tumour resection is frequently performed but adjuvant chemotherapy is rarely prescribed as there are no clearly established standards of care. In a metastatic setting, recent phase III studies have demonstrated that doublet front-line chemotherapy provided no survival benefit. Moreover, several studies have established the benefit of bevacizumab in association with chemotherapy. There is a lack of evidence for the efficacy of anti-epidermal growth factor antibodies in elderly patients. Geriatric assessments could help to select the adequate treatment strategy for individual patients. Geriatric oncology is now the challenge we have to face, and more specific trials are needed.
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Affiliation(s)
- Thomas Aparicio
- Gastroenterology and Digestive Oncology Department, CHU Avicenne, APHP, Bobigny, France.
| | | | - Laurent Quero
- Radiotherapy Department, CHU Saint Louis, APHP, Paris, France
| | - Sylvain Manfredi
- Hepato-Gastroenterology and Oncology Department, INSERM U866, CHU Dijon, Dijon, France
| | - Philippe Wind
- Surgery Department, CHU Avicenne, APHP, Bobigny, France
| | - Elena Paillaud
- Geriatric Department, CHU Henri Mondor, APHP, Créteil, France
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Pinto C, Antonuzzo L, Porcu L, Aprile G, Maiello E, Masi G, Petrelli F, Scartozzi M, Torri V, Barni S. Efficacy and Safety of Bevacizumab Combined With Fluoropyrimidine Monotherapy for Unfit or Older Patients With Metastatic Colorectal Cancer: A Systematic Review and Meta-Analysis. Clin Colorectal Cancer 2016; 16:e61-e72. [PMID: 27687553 DOI: 10.1016/j.clcc.2016.08.006] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Revised: 08/01/2016] [Accepted: 08/18/2016] [Indexed: 01/05/2023]
Abstract
BACKGROUND Whether bevacizumab represents a feasible option for the first-line treatment of unfit and elderly patients with metastatic colorectal cancer (mCRC) remains controversial. The present systematic review and meta-analysis evaluated the efficacy and safety data of bevacizumab combined with first-line fluoropyrimidine monochemotherapy for these complex patients. PATIENTS AND METHODS A systematic search of the published data was conducted through May 31, 2016. The random-effects model was used to combine the effect estimates and the I2 index to quantify the between-study heterogeneity unexplained by sampling error. RESULTS We included 3 randomized controlled trials, 4 single-arm phase II trials, and 1 prospective cohort study in the present meta-analysis (n = 782). The monochemotherapy administered was capecitabine in 531 patients (67.9%) and 5-fluorouracil in 251 (32.1%); 500 (63.9%) also received bevacizumab. The median age was 75 years, 441 patients (56.4%) were men, and the Eastern Cooperative Oncology Group performance status was 0 to 1 in 684 patients (87.7%). The combination with bevacizumab produced advantages in terms of both progression-free survival (hazard ratio, 0.52; 95% confidence interval, 0.43-0.64; P < .00001; I2 = 0%) and overall survival (HR, 0.79; 95% CI, 0.64-0.98; P = .03; I2 = 0%). The pooled effect estimates of the randomized controlled trials have been previously reported. As expected, all-grade hypertension (27% vs. 4.9%), bleeding (24% vs. 6.4%), thromboembolic events (10% vs. 5%), and proteinuria (25.6% vs. 8.2%) were more frequent in the bevacizumab combination group. CONCLUSION Adding bevacizumab to first-line fluoropyrimidine monochemotherapy significantly improved progression-free and overall survival in unfit and elderly patients with mCRC, with a manageable safety profile and no unexpected toxicities.
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Affiliation(s)
- Carmine Pinto
- Department of Medical Oncology, Istituto di Ricovero e Cura a Carattere Scientifico-Arcispedale S. Maria Nuova, Reggio Emilia, Italy.
| | - Lorenzo Antonuzzo
- Department of Medical Oncology, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy
| | - Luca Porcu
- Department of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
| | - Giuseppe Aprile
- Department of Medical Oncology, University and General Hospital, Udine, Italy
| | - Evaristo Maiello
- Oncology Unit, Istituto di Ricovero e Cura a Carattere Scientifico Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Gianluca Masi
- Division of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Fausto Petrelli
- Oncology Unit, Azienda Ospedaliera Treviglio, Treviglio, Italy
| | - Mario Scartozzi
- Department of Oncology, Università di Cagliari-Azienda Ospedaliero Universitaria, Monserrato, Italy
| | - Valter Torri
- Department of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
| | - Sandro Barni
- Oncology Unit, Azienda Ospedaliera Treviglio, Treviglio, Italy
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Population-Based Patterns and Factors Associated With Underuse of Palliative Systemic Therapy in Elderly Patients With Metastatic Colon Cancer. Clin Colorectal Cancer 2016; 16:147-153. [PMID: 27670894 DOI: 10.1016/j.clcc.2016.08.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Revised: 08/08/2016] [Accepted: 08/18/2016] [Indexed: 12/14/2022]
Abstract
BACKGROUND We compared the patterns and factors associated with chemotherapy and bevacizumab use in elderly versus young patients with metastatic colon cancer (mCC) and determined the effect of systemic therapy on overall survival (OS) according to age. MATERIALS AND METHODS Patients diagnosed with mCC from 2009 to 2010 in British Columbia, Canada were reviewed and categorized as elderly patients (age ≥ 70 years) and young patients (age < 70 years). Cox regression models adjusted for age and confounders were used to determine the effect of systemic therapy on OS. RESULTS We identified 1013 patients with a median age of 67 years. Of the 1013 patients, 42% were elderly and 58% were young; 57% were men; and 66% had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1. Fewer elderly patients were offered systemic therapy compared with young patients (48% vs. 77%; P < .001). Among those treated, elderly patients were less likely than young patients to receive combination chemotherapy (47% vs. 81%; P < .0001) and bevacizumab (19% vs. 47%; P < .0001). The most common reasons for no treatment were similar for the elderly and young patients: patient choice, poor ECOG PS, and significant comorbidities. Advanced age alone was also cited as a reason for elderly but not for young patients (7% vs. 0%). When treated, the risk of adverse events and treatment interruptions was comparable between age groups. The receipt of systemic therapy was associated with improved OS in both elderly (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.37-0.56; P < .0001) and young (HR, 0.43; 95% CI, 0.35-0.53; P < .0001) patients, regardless of age (interaction P > .05). CONCLUSION In carefully selected elderly patients, the outcomes from systemic therapy were comparable to those for young patients. Thus, age alone should not be a barrier to treatment of mCC.
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Botrel TEA, Clark LGDO, Paladini L, Clark OAC. Efficacy and safety of bevacizumab plus chemotherapy compared to chemotherapy alone in previously untreated advanced or metastatic colorectal cancer: a systematic review and meta-analysis. BMC Cancer 2016; 16:677. [PMID: 27558497 PMCID: PMC4997727 DOI: 10.1186/s12885-016-2734-y] [Citation(s) in RCA: 84] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Accepted: 06/30/2016] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of neoplasm-related death in the United States. Several studies analyzed the efficacy of bevacizumab combined with different chemotherapy regimens consisting on drugs such as 5-FU, capecitabine, irinotecan and oxaliplatin. This systematic review aims to evaluate the effectiveness and safety of chemotherapy plus bevacizumab versus chemotherapy alone in patients with previously untreated advanced or metastatic colorectal cancer (mCRC). METHODS Several databases were searched, including MEDLINE, EMBASE, LILACS, and CENTRAL. The primary endpoints were overall survival and progression-free survival. Data extracted from the studies were combined by using hazard ratio (HR) or risk ratio (RR) with their corresponding 95 % confidence intervals (95 % CI). RESULTS The final analysis included 9 trials comprising 3,914 patients. Patients who received the combined treatment (chemotherapy + bevacizumab) had higher response rates (RR = 0.89; 95 % CI: 0.82 to 0.96; p = 0.003) with heterogeneity, higher progression-free survival (HR = 0.69; 95 % CI: 0.63 to 0.75; p < 0.00001) and also higher overall survival rates (HR = 0.87; 95 % CI: 0.80 to 0.95; p = 0.002) with moderate heterogeneity. Regarding adverse events and severe toxicities (grade ≥ 3), the group receiving the combined therapy had higher rates of hypertension (RR = 3.56 95 % CI: 2.58 to 4.92; p < 0.00001), proteinuria (RR = 1.89; 95 % CI: 1.26 to 2.84; p = 0.002), gastrointestinal perforation (RR = 3.63; 95 % CI: 1.31 to 10.09; p = 0.01), any thromboembolic events (RR = 1.44; 95 % CI: 1.20 to 1.73; p = 0.0001), and bleeding (RR = 1.81; 95 % CI: 1.22 to 2.67; p = 0.003). CONCLUSION The combination of chemotherapy with bevacizumab increased the response rate, progression-free survival and overall survival of patients with mCRC without prior chemotherapy. The results of progression-free survival (PFS) and overall survival (OS) were comparatively higher in those subgroups of patients receiving bolus 5-FU or capecitabine-based chemotherapy plus bevacizumab, when compared to patients treated with infusional %-FU plus bevacizumab (no difference in PFS and OS). Regarding the type of cytotoxic scheme, regimens containing irinotecan and fluoropyrimidine monotherapy showed superior efficacy results when combined to bevacizumab.
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Affiliation(s)
- Tobias Engel Ayer Botrel
- Evidencias - A Kantar Health Company, Av. José de Souza Campos, 550 - 7°. andar (salas 71 e 72), Nova Campinas, Campinas, São Paulo, Brazil, 13092-123.
- CIOP - Centro Integrado de Oncologia e Pesquisa, Rua Santo Antônio 200, sala 301, Poços de Caldas, Minas Gerais, Brazil, 37701-036.
| | - Luciana Gontijo de Oliveira Clark
- Evidencias - A Kantar Health Company, Av. José de Souza Campos, 550 - 7°. andar (salas 71 e 72), Nova Campinas, Campinas, São Paulo, Brazil, 13092-123
| | - Luciano Paladini
- Evidencias - A Kantar Health Company, Av. José de Souza Campos, 550 - 7°. andar (salas 71 e 72), Nova Campinas, Campinas, São Paulo, Brazil, 13092-123
| | - Otávio Augusto C Clark
- Evidencias - A Kantar Health Company, Av. José de Souza Campos, 550 - 7°. andar (salas 71 e 72), Nova Campinas, Campinas, São Paulo, Brazil, 13092-123
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Bradley CJ, Yabroff KR, Warren JL, Zeruto C, Chawla N, Lamont EB. Trends in the Treatment of Metastatic Colon and Rectal Cancer in Elderly Patients. Med Care 2016; 54:490-7. [DOI: 10.1097/mlr.0000000000000510] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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