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Effect of First-Line Chemotherapy Combined With Cetuximab or Bevacizumab on Overall Survival in Patients With KRAS Wild-Type Advanced or Metastatic Colorectal Cancer: A Randomized Clinical Trial
Open accessAbstract
Importance: Combining biologic monoclonal antibodies with chemotherapeutic cytotoxic drugs provides clinical benefit to patients with advanced or metastatic colorectal cancer, but the optimal choice of the initial biologic therapy in previously untreated patients is unknown. Objective: To determine if the addition of cetuximab vs bevacizumab to the combination of leucovorin, fluorouracil, and oxaliplatin (mFOLFOX6) regimen or the combination of leucovorin, fluorouracil, and irinotecan (FOLFIRI) regimen is superior as first-line therapy in advanced or metastatic KRAS wild-type (wt) colorectal cancer. Design, Setting, and Participants: Patients (≥18 years) enrolled at community and academic centers throughout the National Clinical Trials Network in the United States and Canada (November 2005-March 2012) with previously untreated advanced or metastatic colorectal cancer whose tumors were KRAS wt chose to take either the mFOLFOX6 regimen or the FOLFIRI regimen as chemotherapy and were randomized to receive either cetuximab (n = 578) or bevacizumab (n = 559). The last date of follow-up was December 15, 2015. Interventions: Cetuximab vs bevacizumab combined with either mFOLFOX6 or FOLFIRI chemotherapy regimen chosen by the treating physician and patient. Main Outcomes and Measures: The primary end point was overall survival. Secondary objectives included progression-free survival and overall response rate, site-reported confirmed or unconfirmed complete or partial response. Results: Among 1137 patients (median age, 59 years; 440 [39%] women), 1074 (94%) of patients met eligibility criteria. As of December 15, 2015, median follow-up for 263 surviving patients was 47.4 months (range, 0-110.7 months), and 82% of patients (938 of 1137) experienced disease progression. The median overall survival was 30.0 months in the cetuximab-chemotherapy group and 29.0 months in the bevacizumab-chemotherapy group with a stratified hazard ratio (HR) of 0.88 (95% CI, 0.77-1.01; P = .08). The median progression-free survival was 10.5 months in the cetuximab-chemotherapy group and 10.6 months in the bevacizumab-chemotherapy group with a stratified HR of 0.95 (95% CI, 0.84-1.08; P = .45). Response rates were not significantly different, 59.6% vs 55.2% for cetuximab and bevacizumab, respectively (difference, 4.4%, 95% CI, 1.0%-9.0%, P = .13). Conclusions and Relevance: Among patients with KRAS wt untreated advanced or metastatic colorectal cancer, there was no significant difference in overall survival between the addition of cetuximab vs bevacizumab to chemotherapy as initial biologic treatment. Trial Registration: clinicaltrials.gov identifier: NCT00265850.
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“Also, patients with metastatic colorectal cancer and related intestinal malignancies tend to receive similar treatments and live for many months with relatively stable health (median overall survival >2 years) [44], facilitating study completion and potentially derivation of durable benefit from the intervention.”
From Being present: A single-arm feasibility study of audio-based mindfulness meditation for colorectal cancer patients and caregivers (2018) · cites this paper as [44]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Although a higher percentage of men enrolled compared to most prior mindfulness interventions for integrative cancer care [34], the evaluable study sample included a greater proportion of younger (age <50), female, White and Latino or Hispanic patients relative to the underlying population [44, 53].”
From Being present: A single-arm feasibility study of audio-based mindfulness meditation for colorectal cancer patients and caregivers (2018) · cites this paper as [44]
Experimental — accuracy not yet measuredIn the citing paper
“This trial demonstrated that patients in the cetuximab plus chemotherapy group had slightly higher overall survival versus patients in the bevacizumab plus chemotherapy group (30.0 months versus 29.0 months).”
From Update on Targeted Therapy and Immunotherapy for Metastatic Colorectal Cancer (2024) · cites this paper as [65]
In the citing paper
“Similar to the FIRE-3 trial, median progression-free survival and response rates were similar between groups.”
From Update on Targeted Therapy and Immunotherapy for Metastatic Colorectal Cancer (2024) · cites this paper as [65]
In the citing paper
“Similarly, the CALGB/SWOG 80405 trial showed that both cetuximab and bevacizumab provided comparable outcomes when combined with chemotherapy in the overall population, but the benefit of anti-EGFR therapy was again limited to RAS wild-type tumors [21].”
From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [21]
In the citing paper
“however, it must be noted here that this pooled analysis also included patients who had received a nonstandard treatment regimen, including FUFIRI, FUFOX, and mIROX as induction chemotherapies and bevacizumab monotherapy or observation alone as maintenance therapies in clinical trials [22,23].”
From The Prognostic Impact of KRAS G12C Mutation in Patients with Metastatic Colorectal Cancer: A Multicenter Retrospective Observational Study (2021) · cites this paper as [22]
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“Comparison of OS across trials is difficult because of different trial schedules and times of randomization, which occurred before or after induction chemotherapy; in addition, we enrolled only patients with definitively nonresectable metastases and patients were not selected according to RASmutation, contrary to othe…”
ResultModest, D. P., Denecke, T., Pratschke, J., Ricard, I., Lang, H., Bemelmans, M. H. A., Becker, T., Rentsch, M., Seehofer, D., Bruns, C. J., et al. (2017) · European Journal of Cancer · doi:10.1016/j.ejca.2017.10.028 · Cited by 91
Mauri, G., Pizzutilo, E. G., Amatu, A., Bencardino, K. B., Palmeri, L., Bonazzina, E. F., Tosi, F., Stella, G. C., Burrafato, G., Scaglione, F., et al. (2018) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2018.12.006 · Cited by 90
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Self-citationModest, D. P., Karthaus, M., Fruehauf, S., Graeven, U., Müller, L., König, A. O., von Weikersthal, L. F., Caca, K., Kretzschmar, A., Goekkurt, E., et al. (2021) · Journal of Clinical Oncology · doi:10.1200/jco.21.01332 · Cited by 89
van de Haar, J., Ma, X., Ooft, S., van der Helm, P. W., Hoes, L. R., Mainardi, S., Pinato, D. J., Sun, K., Salvatore, L., Tortora, G., et al. (2023) · Nature Medicine · doi:10.1038/s41591-023-02240-8 · Cited by 92
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Shitara, K., Yamanaka, T., Denda, T., Tsuji, Y., Shinozaki, K., Komatsu, Y., Kobayashi, Y., Furuse, J., Okuda, H., Asayama, M., et al. (2018) · Annals of Oncology · doi:10.1093/annonc/mdy526 · Cited by 83
Deng, S., Gu, J., Jiang, Z., Cao, Y., Mao, F., Xue, Y., Wang, J., Dai, K., Qin, L., Liu, K., et al. (2022) · Journal of Nanobiotechnology · doi:10.1186/s12951-022-01613-4 · Cited by 88
Systemic treatment for metastatic colorectal cancer in the era of precision medicine
Sandhu, J. S., Lavingia, V. K., & Fakih, M. (2019) · Journal of Surgical Oncology · doi:10.1002/jso.25421 · Cited by 80
Chen, E. X., Loree, J. M., Titmuss, E., Jonker, D. J., Kennecke, H. F., Berry, S. R., Couture, F., Ahmad, C. E., Goffin, J. R., Kavan, P., et al. (2023) · JAMA Network Open · doi:10.1001/jamanetworkopen.2023.46094 · Cited by 85
Self-citationTougeron, D., Sueur, B., Zaanan, A., de la Fouchardière, C., Sefrioui, D., Lecomte, T., Aparicio, T., Guetz, G. D., Artru, P., Hautefeuille, V., et al. (2020) · International Journal of Cancer · doi:10.1002/ijc.32879 · Cited by 78
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Lenz, H., Parikh, A. R., Spigel, D. R., Cohn, A. L., Yoshino, T., Kochenderfer, M. D., Élez, E., Shao, S. H., Deming, D. A., Holdridge, R. C., et al. (2024) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2023-008409 · Cited by 83
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Caputo, V., Ciardiello, F., Corte, C. M. D., Martini, G., Troiani, T., & Napolitano, S. (2023) · Exploration of Targeted Anti-tumor Therapy · doi:10.37349/etat.2023.00125 · Cited by 80
Results and challenges of immune checkpoint inhibitors in colorectal cancer
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Smabers, L. P., Wensink, G. E., Veríssimo, C. S., Koedoot, E., Pitsa, K.-C., Huismans, M. A., Barón, C. H., Doorn, M., Iersel, L. V., Cirkel, G. A., et al. (2024) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-024-02980-6 · Cited by 84
“This cut-off was based on the response rate of approximately 60% for patients treated with FOL-FOX in the first line in order to evaluate whether the upper third most resistant PDOs indeed predict failure of FOLFOX [1, 2].”
BackgroundThe role of tumor angiogenesis as a therapeutic target in colorectal cancer
Battaglin, F., Puccini, A., Intini, R., Schirripa, M., Ferro, A., Bergamo, F., Lonardi, S., Zagonel, V., Lenz, H., & Loupakis, F. (2018) · Expert Review of Anticancer Therapy · doi:10.1080/14737140.2018.1428092 · Cited by 75
“CALGB/SWOG 80,405 (III) NCT00265850 [41,42] 1st FOLFIRI/FOLFOX6 + bevacizumab (n.”
ResultSelf-citationTherapeutic Targeting of the Colorectal Tumor Stroma
Fridman, W. H., Miller, I. S., Sautès‐Fridman, C., & Byrne, A. T. (2019) · Gastroenterology · doi:10.1053/j.gastro.2019.09.045 · Cited by 72
Petrelli, F., Ardito, R., Ghidini, A., Zaniboni, A., Ghidini, M., Barni, S., & Tomasello, G. (2018) · Oncology · doi:10.1159/000486338 · Cited by 70
New Strategies Using Antibody Combinations to Increase Cancer Treatment Effectiveness
Corraliza-Gorjón, I., Somovilla-Crespo, B., Santamaría, S. S., García‐Sanz, J. A., & Kremer, L. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01804 · Cited by 70
Onidani, K., Shoji, H., Kakizaki, T., Yoshimoto, S., Okaya, S., Miura, N., Sekikawa, S., Furuta, K., Lim, C. T., Shibahara, T., et al. (2019) · Cancer Science · doi:10.1111/cas.14092 · Cited by 69
Stein, A., Simnica, D., Schultheiß, C., Scholz, R., Tintelnot, J., Goekkurt, E., von Wenserski, L., Willscher, E., Paschold, L., Sauer, M., et al. (2021) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2021-002844 · Cited by 66
Guercio, B. J., Zhang, S., Ou, F., Venook, A. P., Niedzwiecki, D., Lenz, H., Innocenti, F., O’Neil, B. H., Shaw, J. E., Polite, B. N., et al. (2019) · Journal of Clinical Oncology · doi:10.1200/jco.19.01019 · Cited by 70
“During enrollment, the trial underwent major design changes in treatment and KRAS inclusion criteria as a result of evolving science.(22-26) Our cohort includes patients who participated throughout the trial history.”
MethodSelf-citationThe unique immune microenvironment of liver metastases: Challenges and opportunities
Ciner, A., Jones, K. I., Muschel, R. J., & Brodt, P. (2020) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2020.06.003 · Cited by 68
Metastatic Colorectal Cancer. First Line Therapy for Unresectable Disease
Aparicio, J., Esposito, F. M., Serrano, S., Falcó, E., Escudero, P., Ruiz‐Casado, A., Manzano, H., & Montés, A. F. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9123889 · Cited by 71
ctDNA and Adjuvant Therapy for Colorectal Cancer: Time to Re-Invent Our Treatment Paradigm
Naidoo, M., Gibbs, P., & Tie, J. (2021) · Cancers · doi:10.3390/cancers13020346 · Cited by 67
Jiao, J., Zhang, J., Yang, F., Song, W., Han, D., Wen, W., & Qin, W. (2020) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/j.ejpb.2020.05.002 · Cited by 67
Bolhuis, K., Kos, M., van Oijen, M. G. H., Swijnenburg, R., & Punt, C. J. A. (2020) · European Journal of Cancer · doi:10.1016/j.ejca.2020.09.037 · Cited by 66
Yoshino, T., Portnoy, D. C., Obermannova, R. L., Bodoky, G., Prausová, J., García‐Carbonero, R., Ciuleanu, T., Alfonso, P. G., Cohn, A. L., Cutsem, E. V., et al. (2018) · Annals of Oncology · doi:10.1093/annonc/mdy461 · Cited by 64
“The left tumour subgroup had a lower percentage of females and mutant RAS tumours than the right tumour sub-group, consistent with previously published data [7, 15].”
ResultYuan, C., Sato, K., Hollis, B. W., Zhang, S., Niedzwiecki, D., Ou, F., Chang, I.-W., O’Neil, B. H., Innocenti, F., Lenz, H., et al. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-0877 · Cited by 64
“Full details and results of the treatment trial have been described previously (14).”
BackgroundSelf-citationBitar, S. A., El-Sabban, M. E., Doughan, S., & Abou-Kheir, W. G. (2023) · World Journal of Gastroenterology · doi:10.3748/wjg.v29.i9.1395 · Cited by 69
Oki, E., Emi, Y., Yamanaka, T., Uetake, H., Muro, K., Takahashi, T., Nagasaka, T., Hatano, E., Ojima, H., Manaka, D., et al. (2019) · British Journal of Cancer · doi:10.1038/s41416-019-0518-2 · Cited by 62
Gupta, R., Meric‐Bernstam, F., Rothe, M., Garrett-Mayer, E. S., Mangat, P. K., D’Andre, S. D., Ahn, E. R., O'Lone, R., Halabi, S., Grantham, G. N., et al. (2022) · JCO Precision Oncology · doi:10.1200/po.22.00306 · Cited by 72
Self-citationPan, M., Jiang, C., Tse, P., Achacoso, N., Alexeeff, S., Solorzano, A. V., Chung, E., Hu, W., Truong, T.-G., Arora, A., et al. (2021) · Journal of Clinical Oncology · doi:10.1200/jco.21.02014 · Cited by 59
“In addition, our findings suggest that a reanalysis, using mutp53 GOF and non-GOF as additional biomarkers, of the previously completed large clinical trials evaluating the efficacy of cetuximab and bevacizumab plus chemotherapy may reveal additional insight.(31,32,36,37,52-54) Future CRC clinical trials may benefit f…”
ResultCharlton, M. E., Kahl, A. R., Greenbaum, A. A., Karlitz, J. J., Lin, C. H., Lynch, C. F., & Chen, V. W. (2017) · Journal of the National Comprehensive Cancer Network · doi:10.6004/jnccn.2017.7011 · Cited by 58
Wang, F., He, M.-M., Wang, Z., Su, L., Jin, Y., Ren, C., Shi, S., Bi, B., Chen, S.-Z., Lv, Z.-D., et al. (2019) · BMC Cancer · doi:10.1186/s12885-019-5696-z · Cited by 57
Implications of Selection Bias Due to Delayed Study Entry in Clinical Genomic Studies
Brown, S., Lavery, J. A., Shen, R., Martin, A. S., Kehl, K. L., Sweeney, S. M., Lepisto, E. M., Rizvi, H. A., McCarthy, C. G., Schultz, N. D., et al. (2021) · JAMA Oncology · doi:10.1001/jamaoncol.2021.5153 · Cited by 55
Self-citationResistance to targeted therapy in metastatic colorectal cancer: Current status and new developments
Tang, Y., Li, D., Duan, J.-Y., Sheng, L., & Wang, X. (2023) · World Journal of Gastroenterology · doi:10.3748/wjg.v29.i6.926 · Cited by 58
Curcumin: A therapeutic strategy for colorectal cancer?
de Porras, V. R., Layos, L., & Martinez‐Balibrea, E. (2020) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2020.09.004 · Cited by 58
van der Werf, A., Langius, J. A. E., Beeker, A., ten Tije, A. J., Vulink, A. J. E., Haringhuizen, A., Berkhof, J. H., van der Vliet, H. J., Verheul, H. M. W., & de van der Schueren, M. A. E. (2020) · Clinical Nutrition · doi:10.1016/j.clnu.2020.01.009 · Cited by 57
Explaining the unexplainable: discrepancies in results from the CALGB/SWOG 80405 and FIRE-3 studies
Aderka, D., Stintzing, S., & Heinemann, V. (2019) · The Lancet Oncology · doi:10.1016/s1470-2045(19)30172-x · Cited by 55
Targeted therapy for metastatic colorectal cancer
Price, T. J., Tang, M., Gibbs, P., Haller, D. G., Peeters, M., Arnold, D., Segelov, E., Roy, A. C., Tebbutt, N. C., Pavlakis, N., et al. (2018) · Expert Review of Anticancer Therapy · doi:10.1080/14737140.2018.1502664 · Cited by 54
Predicting Chemotherapy Toxicity and Death in Older Adults with Colon Cancer: Results of MOST Study
Rétornaz, F., Guillem, O., Rousseau, F., Morvan, F., Rinaldi, Y., Nahon, S., Castagna, C., Boulahssass, R., Grino, M., & Gholam, D. (2019) · The Oncologist · doi:10.1634/theoncologist.2019-0241 · Cited by 57
Metadata
- Authors
- Venook, A. P., Niedzwiecki, D., Lenz, H.-J., Innocenti, F., Fruth, B., Meyerhardt, J. A., Schrag, D., Greene, C., O'Neil, B. H., Atkins, J. N., Berry, S., Polite, B. N., O'Reilly, E. M., Goldberg, R. M., Hochster, H. S., Schilsky, R. L., Bertagnolli, M. M., El-Khoueiry, A. B., Watson, P., Benson, A. B., Mulkerin, D. L., Mayer, R. J., & Blanke, C.
- Affiliations
- University of California, San Francisco (US)
- Duke University (US)
- University of Southern California (US)
- University of North Carolina at Chapel Hill (US)
- Mayo Clinic (US)
- Dana-Farber/Partners CancerCare, Boston, Massachusetts
- Indiana University, Simon Cancer Center, Indianapolis
- Southeastern Medical Oncology Center (US)
- Sunnybrook Health Science Centre (CA)
- University of Chicago Comprehensive Cancer Center, Chicago, Illinois
- Memorial Sloan Kettering Cancer Center (US)
- The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (US)
- Department of Medical Oncology, Yale University School of Medicine, New Haven, Connecticut
- American Society of Clinical Oncology (US)
- Brigham and Women's Hospital (US)
- Kinston Medical Specialists (US)
- Northwestern University (US)
- University of Wisconsin–Madison (US)
- Oregon Health & Science University (US)
- ORCID
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2017-06-20
- Volume
- 317
- Issue
- 23
- Pages
- 2392
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- PMC
- PMC5545896
- OpenAlex
- W2712978371
- Cited by
- 898
- References
- 24
- Citations by year
- 2026: 66 · 2025: 76 · 2024: 87 · 2023: 104 · 2022: 118 · 2021: 118 · 2020: 122 · 2019: 107 · 2018: 82 · 2017: 16
- FWCI
- 39.43
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (UL1TR001863)
- National Cancer Institute (U10CA180882, K05CA169384, U10CA180820, U10CA180791, U10CA180888, U10CA180836, U10CA180790, U10CA180830, U10CA180795, U10CA180850, R01CA149222, U10CA180838, U10CA180867, U10CA180821, U10CA180799)
- National Center for Advancing Translational Sciences
- 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, KRAS wild-type, cetuximab, bevacizumab, first-line chemotherapy, mFOLFOX6, FOLFIRI, oxaliplatin, irinotecan, monoclonal antibodies, overall survival, progression-free survival, anti-EGFR therapy, anti-VEGF therapy, community oncology
- MeSH terms
- Bevacizumab, Cetuximab, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Camptothecin, Canada, Leucovorin, Female, Fluorouracil, Humans, Male, Middle Aged, Organoplatinum Compounds, Genes, ras, United States, Colorectal Neoplasms, Treatment Outcome, Disease-Free Survival, Angiogenesis Inhibitors, Kaplan-Meier Estimate
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