Maintenance strategies after first-line oxaliplatin plus fluoropyrimidine plus bevacizumab for patients with metastatic colorectal cancer (AIO 0207): A randomised, non-inferiority, open-label, phase 3 trial
Abstract
Background The definition of a best maintenance strategy following combination chemotherapy plus bevacizumab in metastatic colorectal cancer is unclear. We investigated whether no continuation of therapy or bevacizumab alone are non-inferior to fluoropyrimidine plus bevacizumab, following induction treatment with a fluoropyrimidine plus oxaliplatin plus bevacizumab.Methods In this open-label, non-inferiority, randomised phase 3 trial, we included patients aged 18 years or older with histologically confirmed, previously untreated metastatic colorectal cancer, Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, adequate bone marrow, liver, and renal function, no pre-existing neuropathy greater than grade 1, and measurable disease, from 55 hospitals and 51 private practices in Germany. After 24 weeks of induction therapy with either fluorouracil plus leucovorin plus oxaliplatin or capecitabine plus oxaliplatin, both with bevacizumab, patients without disease progression were randomly assigned centrally by fax (1:1:1) to standard maintenance treatment with a fluoropyrimidine plus bevacizumab, bevacizumab alone, or no treatment. Both patients and investigators were aware of treatment assignment. Stratification criteria were response status, termination of oxaliplatin, previous adjuvant treatment with oxaliplatin, and ECOG performance status. At first progression, re-induction with all drugs of the induction treatment was a planned part of the protocol. Time to failure of strategy was the primary endpoint, defined as time from randomisation to second progression after maintenance (and if applicable re-induction), death, or initiation of further treatment including a new drug. Time to failure of strategy was equivalent to time to first progression for patients who did not receive re-induction (for any reason). The boundary for assessment of non-inferiority was upper limit of the one-sided 98·8% CI 1·43. Analyses were done by intention to treat. The study has completed recruitment, but follow-up of participants is ongoing. The trial is registered with ClinicalTrials.gov, number NCT00973609.Findings Between Sept 17, 2009, and Feb 21, 2013, 837 patients were enrolled and 472 randomised; 158 were randomly assigned to receive fluoropyrimidine plus bevacizumab, 156 to receive bevacizumab monotherapy, and 158 to receive no treatment. Median follow-up from randomisation is 17·0 months (IQR 9·5-25·4). Median time to failure of strategy was 6·9 months (95% CI 6·1-8·5) for the fluoropyrimidine plus bevacizumab group, 6·1 months (5·3-7·4) for the bevacizumab alone group, and 6·4 months (4·8-7·6) for the no treatment group. Bevacizumab alone was non-inferior to standard fluoropyrimidine plus bevacizumab (hazard ratio [HR] 1·08 [95% CI 0·85-1·37]; p=0·53; upper limit of the one-sided 99·8% CI 1·42), whereas no treatment was not (HR 1·26 [0·99-1·60]; p=0·056; upper limit of the one-sided 99·8% CI 1·65). The protocol-defined re-induction after first progression was rarely done (30 [19%] patients in the fluoropyrimidine plus bevacizumab group, 67 [43%] in the bevacizumab monotherapy group, and 73 [46%] in the no treatment group. The most common grade 3 adverse event was sensory neuropathy (21 [13%] of 158 patients in the fluoropyrimidine plus bevacizumab group, 22 [14%] of 156 patients in the bevacizumab alone group, and 12 [8%] of 158 patients in the no treatment group).Interpretation Although non-inferiority for bevacizumab alone was demonstrated for the primary endpoint, maintenance treatment with a fluoropyrimidine plus bevacizumab may be the preferable option for patients following an induction treatment with a fluoropyrimidine, oxaliplatin, and bevacizumab, as it allows the planned discontinuation of the initial combination without compromising time with controlled disease. Only a few patients were exposed to re-induction treatment, thus deeming the primary endpoint time to failure of strategy non-informative and clinically irrelevant. Progression-free survival and overall survival should be considered primary endpoints in future trials exploring maintenance strategies.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In AIO-KRK-0207, subgroup analysis for mPFS showed significant advantage in wild-type tumor patients receiving bevacizumab maintenance versus those who did not (HR 2.21, 95% CI 1.38-3.52).
“In the AIO-KRK-0207 study, subgroup analysis for mPFS demonstrated a significant advantage in patients with wild-type tumors who received bevacizumab maintenance therapy compared to those who did not (HR 2.21, 95% CI 1.38–3.52) [38].”
From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [38]
In AIO-KRK-0207, no significant difference was observed in patients with RAS or BRAF mutations (HR 1.19, 95% CI 0.84-1.70).
“However, no significant difference was observed in patients with RAS or BRAF mutations (HR 1.19, 95% CI 0.84–1.70).”
From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [38]
Cites
Bevacizumab plus Irinotecan, Fluorouracil, and Leucovorin for Metastatic Colorectal Cancer
Hurwitz, H., Fehrenbacher, L., Novotny, W., Cartwright, T., Hainsworth, J., Heim, W., Berlin, J., Baron, A., Griffing, S., Holmgren, E., et al. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa032691 · Cited by 10,968 · see citing works
Saltz, L. B., Clarke, S., Díaz-Rubio, E., Scheithauer, W., Figer, A., Wong, R., Koski, S., Lichinitser, M., Yang, T.-S., Rivera, F., et al. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2007.14.9930 · Cited by 2,955 · see citing works
Heinemann, V., von Weikersthal, L. F., Decker, T., Kiani, A., Vehling-Kaiser, U., Al-Batran, S.-E., Heintges, T., Lerchenmüller, C., Kahl, C., Seipelt, G., et al. (2014) · The Lancet Oncology · doi:10.1016/s1470-2045(14)70330-4 · Cited by 1,740 · see citing works
Self-citationVan Cutsem, E., Cervantes, A., Nordlinger, B., & Arnold, D. (2014) · Annals of Oncology · doi:10.1093/annonc/mdu260 · Cited by 1,167 · see citing works
Self-citationTournigand, C., Cervantes, A. M. R., Figer, A., Lledo, G., Flesch, M., Buyse, M. E., Mineur, L., Carola, É., Etienne, P.-L., Rivera, F., et al. (2006) · Journal of Clinical Oncology · doi:10.1200/jco.2005.03.0106 · Cited by 802 · see citing works
Cunningham, D., Láng, I., Marcuello, E., Lorusso, V., Ocvirk, J., Shin, D. B., Jonker, D. J., Osborne, S., Andre, N., Waterkamp, D., et al. (2013) · The Lancet Oncology · doi:10.1016/s1470-2045(13)70154-2 · Cited by 641 · see citing works
Simkens, L. H. J., van Tinteren, H., May, A. M., ten Tije, A. J., Creemers, G., Loosveld, O. J. L., de Jongh, F. E., Erdkamp, F., Erjavec, Z., van der Torren, A. M. E., et al. (2015) · The Lancet · doi:10.1016/s0140-6736(14)62004-3 · Cited by 522 · see citing works
Venook, A. P., Niedzwiecki, D., Lenz, H., Innocenti, F., Mahoney, M. R., O’Neil, B. H., Shaw, J. E., Polite, B. N., Höchster, H. S., Atkins, J. N., et al. (2014) · Journal of Clinical Oncology · doi:10.1200/jco.2014.32.18_suppl.lba3 · Cited by 428 · see citing works
Tebbutt, N. C., Wilson, K., Gebski, V. J., Cummins, M. M., Zannino, D., van Hazel, G. A., Robinson, B., Broad, A., Ganju, V., Ackland, S. P., et al. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2009.27.7723 · Cited by 413 · see citing works
Chibaudel, B., Maindrault‐Gœbel, F., Lledo, G., Mineur, L., André, T., Bennamoun, M., Mabro, M., Artru, P., Carola, É., Flesch, M., et al. (2009) · Journal of Clinical Oncology · doi:10.1200/jco.2009.23.4344 · Cited by 394 · see citing works
Díaz‐Rubio, E., Gómez‐España, A., Massutí, B., Sastre, J., Abad, A., Valladares, M., Rivera, F., Safont, M. J., de Prado, P. M., Gallén, M., et al. (2012) · The Oncologist · doi:10.1634/theoncologist.2011-0249 · Cited by 210 · see citing works
Koeberle, D., Betticher, D. C., von Moos, R., Dietrich, D., Brauchli, P., Baertschi, D., Matter-Walstra, K. W., Winterhalder, R., Borner, M., Anchisi, S., et al. (2015) · Annals of Oncology · doi:10.1093/annonc/mdv011 · Cited by 141 · see citing works
Tournigand, C., Chibaudel, B., Samson, B., Scheithauer, W., Vernerey, D., Mésange, P., Lledo, G., Viret, F., Ramée, J., Tubiana-Mathieu, N., et al. (2015) · The Lancet Oncology · doi:10.1016/s1470-2045(15)00216-8 · Cited by 123 · see citing works
Lenz, H., Niedzwiecki, D., Innocenti, F., Blanke, C. D., Mahony, M. R., O’Neil, B. H., Shaw, J. E., Polite, B. N., Höchster, H. S., Atkins, J., et al. (2014) · Annals of Oncology · doi:10.1093/annonc/mdu438.13 · Cited by 110 · see citing works
Johnsson, A., Hagman, H., Frödin, J., Berglund, Å., Keldsen, N., Fernebro, E., Sundberg, J., Christensen, R. D., Spindler, K.-L. G., Bergström, D., et al. (2013) · Annals of Oncology · doi:10.1093/annonc/mdt236 · Cited by 76 · see citing works
Yalçın, Ş., Uslu, R., Dane, F., Yılmaz, U., Zengin, N., Büyükünal, E., Buyukberber, S., Camcı, C., Şencan, O., Kılıçkap, S., et al. (2013) · Oncology · doi:10.1159/000355914 · Cited by 71 · see citing works
Berry, S. R., Cosby, R., Asmis, T. R., Chan, K., Hammad, N., & Krzyzanowska, M. K. (2014) · Annals of Oncology · doi:10.1093/annonc/mdu272 · Cited by 62 · see citing works
Chibaudel, B., Bonnetain, F., Shi, Q., Buyse, M. E., Tournigand, C., Sargent, D. J., Allegra, C. J., Goldberg, R. M., & de Gramont, A. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2011.35.5867 · Cited by 59 · see citing works
Core business, future direction, and the 10-bar target
Tabernero, J. M. (2014) · Annals of Oncology · doi:10.1093/annonc/mdu136 · Cited by 3 · see citing works
Quidde, J., Arnold, D., Hegewisch-Becker, S., et al. (2014) · Annals of Oncology · doi:10.1093/annonc/mdu333.25 · Cited by 2 · see citing works
Self-citationArnold, D., Zurlo, A., Salazar, R., et al. (2014) · Annals of Oncology · doi:10.1093/annonc/mdu342.30 · Cited by 1 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
ESMO consensus guidelines for the management of patients with metastatic colorectal cancer
Van Cutsem, E., Cervantes, A., Adam, R., Sobrero, A., Van Krieken, J. H., Aderka, D., Aranda Aguilar, E., Bardelli, A., Benson, A., Bodoky, G., et al. (2016) · Annals of Oncology · doi:10.1093/annonc/mdw235 · Cited by 3,421 · see citing works
Self-citationComprehensive review of targeted therapy for colorectal cancer
Xie, Y.-H., Chen, Y.-X., & Fang, J.-Y. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-0116-z · Cited by 1,687 · see citing works
From tumour heterogeneity to advances in precision treatment of colorectal cancer
Punt, C. J. A., Koopman, M., & Vermeulen, L. (2017) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2016.171 · Cited by 654 · see citing works
Modest, D. P., Ricard, I., Heinemann, V., Hegewisch-Becker, S., Schmiegel, W., Porschen, R., Stintzing, S., Graeven, U., Arnold, D., von Weikersthal, L. F., et al. (2016) · Annals of Oncology · doi:10.1093/annonc/mdw261 · Cited by 351 · see citing works
Self-citationCremolini, C., Antoniotti, C., Rossini, D., Lonardi, S., Loupakis, F., Pietrantonio, F., Bordonaro, R., Latiano, T. P., Tamburini, E., Santini, D., et al. (2020) · The Lancet Oncology · doi:10.1016/s1470-2045(19)30862-9 · Cited by 334 · see citing works
Aparicio, T., Ghiringhelli, F., Boige, V., Le Malicot, K., Taieb, J., Bouché, O., Phelip, J.-M., François, E., Borel, C., Faroux, R., et al. (2018) · Journal of Clinical Oncology · doi:10.1200/jco.2017.75.2931 · Cited by 91 · see citing works
Salvatore, L., Bria, E., Sperduti, I., Hinke, A., Hegewisch-Becker, S., Aparicio, T., Le Malicot, K., Boige, V., Koeberle, D., Baertschi, D., et al. (2021) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2021.102202 · Cited by 26 · see citing works
Self-citationStahler, A., Heinemann, V., Ricard, I., von Einem, J. C., Giessen-Jung, C., Westphalen, C. B., Michl, M., Heinrich, K., Miller-Phillips, L., Jelas, I., et al. (2020) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-020-03290-y · Cited by 21 · see citing works
Stahler, A., Hoppe, B., Na, I.-K., Keilholz, L., Müller, L., Karthaus, M., Fruehauf, S., Graeven, U., Fischer von Weikersthal, L., Goekkurt, E., et al. (2023) · Journal of Clinical Oncology · doi:10.1200/jco.22.02582 · Cited by 16 · see citing works
Self-citationBlood Vessel-Targeted Therapy in Colorectal Cancer: Current Strategies and Future Perspectives
Jacobsen, A., Siebler, J., Grützmann, R., Stürzl, M., & Naschberger, E. (2024) · Cancers · doi:10.3390/cancers16050890 · Cited by 11 · see citing works
Sütcüoğlu, O., Yıldırım, H. Ç., Almuradova, E., Günenç, D., & Yalçın, Ş. (2025) · Medicina · doi:10.3390/medicina61071202 · Cited by 10 · see citing works
- Authors
- Hegewisch-Becker, S., Graeven, U., Lerchenmüller, C. A., Killing, B., Depenbusch, R., Steffens, C.-C., Al-Batran, S.-E., Lange, T., Dietrich, G., Stoehlmacher, J., Tannapfel, A., Reinacher-Schick, A., Quidde, J., Trarbach, T., Hinke, A., Schmoll, H.-J., & Arnold, D.
- Affiliations
- Kliniken Maria Hilf (DE)
- Lahn-Dill-Kreis (DE)
- Asklepios Klinik Weißenfels (DE)
- University of Bonn (DE)
- Ruhr University Bochum (DE)
- University Medical Center Hamburg-Eppendorf (DE)
- Iomedico (Germany) (DE)
- WiSP Wissenschaftlicher Service Pharma GmbH (Germany) (DE)
- University Hospital in Halle (DE)
- University Medical Center Freiburg (DE)
- ORCID
- Venue
- The Lancet Oncology
- Publisher
- Elsevier BV
- Published
- 2015-10
- Volume
- 16
- Issue
- 13
- Pages
- 1355-1369
- ISSN
- 1470-2045 (ISSN-L)
- OpenAlex
- W2153211112
- Cited by
- 251
- References
- 21
- Citations by year
- 2026: 8 · 2025: 11 · 2024: 13 · 2023: 21 · 2022: 25 · 2021: 22 · 2020: 27 · 2019: 24 · 2018: 30 · 2017: 31 · 2016: 27 · 2015: 12
- FWCI
- 14.50
- Type
- journal article
- Language
- en
- Update notices
- erratum (2015-12-01)
- Open access
- closed
- Locations
- The Lancet Oncology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Oncology › Colorectal Cancer Surgical Treatments
- Health Sciences › Medicine › Surgery › Intraperitoneal and Appendiceal Malignancies
- Keywords
- metastatic colorectal cancer, maintenance therapy, bevacizumab, oxaliplatin, fluoropyrimidine, capecitabine, 5-fluorouracil, leucovorin, non-inferiority, reinduction chemotherapy, first-line chemotherapy, progression-free survival, FOLFOX
- MeSH terms
- Bevacizumab, Capecitabine, Oxaliplatin, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Leucovorin, Female, Fluorouracil, Germany, Humans, Male, Middle Aged, Neoplasm Metastasis, Organoplatinum Compounds, Risk Factors, Time Factors, Colorectal Neoplasms, Treatment Failure, Disease Progression, Angiogenesis Inhibitors, Kaplan-Meier Estimate, Intention to Treat Analysis, Drug Substitution, Maintenance Chemotherapy
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
