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      Panitumumab Plus Fluorouracil and Folinic Acid Versus Fluorouracil and Folinic Acid Alone as Maintenance Therapy in RAS Wild-Type Metastatic Colorectal Cancer: The Randomized PANAMA Trial (AIO KRK 0212)

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          Abstract

          PURPOSE

          The randomized PANAMA trial investigated the efficacy of panitumumab (Pmab) when added to maintenance therapy with fluorouracil and folinic acid (FU/FA) in patients with RAS wild-type metastatic colorectal cancer.

          METHODS

          Following first-line induction therapy with six cycles of FU/FA and oxaliplatin plus Pmab, responding patients (stable disease or partial or complete remission) were randomly assigned (1:1, open-label) to maintenance treatment with either FU/FA plus Pmab or FU/FA alone. The primary objective was to demonstrate superiority of progression-free survival (PFS, time from random assignment until progression or death) in favor of FU/FA plus Pmab with a hazard ratio (HR) of 0.75, a power of 80%, and a significance level of 10%. Secondary end points included overall survival, objective response rate of maintenance therapy, and toxicity. Survival end points were analyzed by the Kaplan-Meier method and compared by log-rank test and Cox regressions. Dichotomous variables were compared by Fisher's exact test; odds ratios were indicated when appropriate. The trial is registered with ClinicalTrials.gov ( NCT01991873).

          RESULTS

          Overall, 248 patients were randomly assigned and received maintenance therapy with either FU/FA plus Pmab (125 patients) or FU/FA alone (123 patients). At data cutoff, with 218 events (of 218 needed), PFS of maintenance therapy was significantly improved with FU/FA plus Pmab (8.8 months v 5.7 months; HR, 0.72; 80% CI, 0.60 to 0.85; P = .014). Overall survival (event rate 54%) numerically favored the FU/FA plus Pmab arm (28.7 months v 25.7 months; HR, 0.84; 95% CI, 0.60 to 1.18; P = .32). Objective response rates were 40.8% in patients receiving FU/FA plus Pmab versus 26.0% in patients receiving FU/FA alone (odds ratio, 1.96; 95% CI, 1.14 to 3.36; P = .02). The most frequent Common Terminology Criteria for Adverse Event grade ≥ 3 event during maintenance therapy was skin rash (7.2%).

          CONCLUSION

          In RAS wild-type metastatic colorectal cancer, maintenance therapy with FU/FA plus Pmab induced a significantly superior PFS compared with FU/FA alone. If active maintenance therapy is aspired following induction therapy with FU/FA and oxaliplatin plus Pmab, FU/FA plus Pmab appears to be the most favorable option.

          Abstract

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          Most cited references37

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          Pembrolizumab in Microsatellite-Instability–High Advanced Colorectal Cancer

          Programmed death 1 (PD-1) blockade has clinical benefit in microsatellite-instability-high (MSI-H) or mismatch-repair-deficient (dMMR) tumors after previous therapy. The efficacy of PD-1 blockade as compared with chemotherapy as first-line therapy for MSI-H-dMMR advanced or metastatic colorectal cancer is unknown.
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            ESMO consensus guidelines for the management of patients with metastatic colorectal cancer.

            Colorectal cancer (CRC) is one of the most common malignancies in Western countries. Over the last 20 years, and the last decade in particular, the clinical outcome for patients with metastatic CRC (mCRC) has improved greatly due not only to an increase in the number of patients being referred for and undergoing surgical resection of their localised metastatic disease but also to a more strategic approach to the delivery of systemic therapy and an expansion in the use of ablative techniques. This reflects the increase in the number of patients that are being managed within a multidisciplinary team environment and specialist cancer centres, and the emergence over the same time period not only of improved imaging techniques but also prognostic and predictive molecular markers. Treatment decisions for patients with mCRC must be evidence-based. Thus, these ESMO consensus guidelines have been developed based on the current available evidence to provide a series of evidence-based recommendations to assist in the treatment and management of patients with mCRC in this rapidly evolving treatment setting.
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              Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study.

              To evaluate the efficacy and safety of bevacizumab when added to first-line oxaliplatin-based chemotherapy (either capecitabine plus oxaliplatin [XELOX] or fluorouracil/folinic acid plus oxaliplatin [FOLFOX-4]) in patients with metastatic colorectal cancer (MCRC). Patients with MCRC were randomly assigned, in a 2 x 2 factorial design, to XELOX versus FOLFOX-4, and then to bevacizumab versus placebo. The primary end point was progression-free survival (PFS). A total of 1,401 patients were randomly assigned in this 2 x 2 analysis. Median progression-free survival (PFS) was 9.4 months in the bevacizumab group and 8.0 months in the placebo group (hazard ratio [HR], 0.83; 97.5% CI, 0.72 to 0.95; P = .0023). Median overall survival was 21.3 months in the bevacizumab group and 19.9 months in the placebo group (HR, 0.89; 97.5% CI, 0.76 to 1.03; P = .077). Response rates were similar in both arms. Analysis of treatment withdrawals showed that, despite protocol allowance of treatment continuation until disease progression, only 29% and 47% of bevacizumab and placebo recipients, respectively, were treated until progression. The toxicity profile of bevacizumab was consistent with that documented in previous trials. The addition of bevacizumab to oxaliplatin-based chemotherapy significantly improved PFS in this first-line trial in patients with MCRC. Overall survival differences did not reach statistical significance, and response rate was not improved by the addition of bevacizumab. Treatment continuation until disease progression may be necessary in order to optimize the contribution of bevacizumab to therapy.
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                Author and article information

                Journal
                J Clin Oncol
                J Clin Oncol
                jco
                JCO
                Journal of Clinical Oncology
                Wolters Kluwer Health
                0732-183X
                1527-7755
                1 January 2022
                17 September 2021
                : 40
                : 1
                : 72-82
                Affiliations
                [ 1 ]Department of Hematology, Oncology and Tumorimmunology, Charité-Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
                [ 2 ]German Cancer Consortium (DKTK), German Cancer Research Centre (DKFZ), Heidelberg, Germany
                [ 3 ]Department of Hematology and Oncology, Munich Hospital Neuperlach, Munich, Germany
                [ 4 ]Dr Hancken Hospital, Stade, Germany
                [ 5 ]Kliniken Maria Hilf GmbH, Mönchengladbach, Germany
                [ 6 ]Oncology Practice UnterEms, Leer, Germany
                [ 7 ]Department of Gastroenterology, University Medicine Göttingen, Göttingen, Germany
                [ 8 ]Gesundheitszentrum St Marien, Amberg, Germany
                [ 9 ]Department of Gastroenterology, Hematology and Oncology, Hospital Ludwigsburg, Ludwigsburg, Germany
                [ 10 ]MVZ Mitte, Leipzig, Germany
                [ 11 ]Practice of Hematology and Oncology (HOPE), Hamburg, Germany
                [ 12 ]University Cancer Center Hamburg (UCCH), Hamburg, Germany
                [ 13 ]Department of Hematology and Oncology, Friedrich-Ebert-Hospital, Neumünster, Germany
                [ 14 ]ClinAssess GmbH, Leverkusen, Germany
                [ 15 ]Charité Universitätsmedizin, Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Pathology, Berlin, Germany
                [ 16 ]St Joseph Hospital, Bochum, Germany
                [ 17 ]Department of Medical Oncology, West German Cancer Center, Westdeutsches Tumorzentrum, University Hospital of Essen, Essen, Germany
                [ 18 ]Department of Medicine III and Comprehensive Cancer Center, University Hospital (LMU), Munich, Germany
                [ 19 ]Zentrum für Tumorbiologie und Integrative Medizin, Klinikum Wilhelmshaven, Wilhelmshaven, Germany
                Author notes
                Dominik Paul Modest, Department of Hematology, Oncology, and Tumorimmunology (CVK), Charité-Universitätsmedizin Berlin, Augustenburgerplatz 1, 13353 Berlin, Germany; e-mail: dominik.modest@ 123456charite.de .
                Article
                JCO.21.01332 00010
                10.1200/JCO.21.01332
                8683209
                34533973
                b3e08beb-ecae-4b87-b224-e45ff5d90006
                © 2021 by American Society of Clinical Oncology

                Creative Commons Attribution Non-Commercial No Derivatives 4.0 License: http://creativecommons.org/licenses/by-nc-nd/4.0/

                History
                : 31 May 2021
                : 3 August 2021
                : 19 August 2021
                Page count
                Figures: 6, Tables: 7, Equations: 0, References: 36, Pages: 0
                Categories
                ORIGINAL REPORTS
                Gastrointestinal Cancer

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