Research Papers:

Exploring the effect of primary tumor sidedness on therapeutic efficacy across treatment lines in patients with metastatic colorectal cancer: analysis of FIRE-3 (AIOKRK0306)

Dominik Paul Modest _, Sebastian Stintzing, Ludwig Fischer von Weikersthal, Thomas Decker, Alexander Kiani, Ursula Vehling-Kaiser, Salah-Eddin Al-Batran, Tobias Heintges, Christoph Kahl, Gernot Seipelt, Frank Kullmann, Werner Scheithauer, Markus Moehler, Julian Walter Holch, Jobst von Einem, Swantje Held and Volker Heinemann

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Oncotarget. 2017; 8:105749-105760. https://doi.org/10.18632/oncotarget.22396

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Dominik Paul Modest1,2, Sebastian Stintzing1,2, Ludwig Fischer von Weikersthal3, Thomas Decker4, Alexander Kiani5, Ursula Vehling-Kaiser6, Salah-Eddin Al-Batran7, Tobias Heintges8, Christoph Kahl9, Gernot Seipelt10, Frank Kullmann11, Werner Scheithauer12, Markus Moehler13,14, Julian Walter Holch1,2, Jobst Christian von Einem1,2, Swantje Held15 and Volker Heinemann1,2

1Department of Medicine III, University Hospital, LMU Munich, Munich, Germany

2German Cancer Consortium (DKTK), German Cancer Research Centre (DKFZ), Heidelberg, Germany

3Gesundheitszentrum St. Marien, Amberg, Germany

4Oncological Practice, Ravensburg, Germany

5Medizinische Klinik IV, Klinikum Bayreuth, Bayreuth, Germany

6Oncological Practice, Landshut, Germany

7Department of Hematology and Oncology, Krankenhaus Nordwest Frankfurt/Main, Frankfurt, Germany

8Department of Medicine II, Städtisches Klinikum Neuss, Neuss, Germany

9Haematology and Oncology, Staedtisches Klinikum Magdeburg, Magdeburg, Germany

10Oncological Practice, Bad Soden, Germany

11Department of Medicine I, Klinikum Weiden, Weiden in der Oberpfalz, Germany

12Department of Internal Medicine I & Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria

13Medical Department 1, Johannes-Gutenberg Universität Mainz, Mainz, Germany

14University Cancer Center Frankfurt/Mainz and German Cancer Consortium (DKTK), Heidelberg, Germany

15ClinAssess GmbH, Leverkusen, Germany

Correspondence to:

Dominik Paul Modest, email: [email protected]

Keywords: colorectal cancer; tumor sidedness; EGFR antibody; bevacizumab; sequential therapy

Received: July 31, 2017    Accepted: October 13, 2017    Published: November 11, 2017


Purpose: To assess the impact of primary tumor sidedness on outcome of patients with metastatic colorectal cancer (mCRC) across treatment lines.

Patients and Methods: Patients of the FIRE-3 trial (initial FOLFIRI plus either cetuximab or bevacizumab) were separately evaluated according to primary tumor site differentiating left-sided (LPT) from right-sided primary tumors (RPT). Efficacy (i.e. progression-free survival (PFS2nd) and overall survival (OS2nd) of second-line therapy) was evaluated by Kaplan-Meier method and compared by log rank test as well as Cox regression analyses. All analyses were also reported according to drug sequences.

Results: 411 of 592 patients (69%) with KRAS exon 2 wild-type tumors received 2nd-line therapy has and had available information on primary tumor location, of those 309 patients (75%) presented with LPT. In patients with LPT, PFS2nd was markedly longer than in patients with RPT (6.0 months [95% CI 5.5-6.5] versus 3.8 months [95% CI 2.5-5.2], hazard ratio: 0.61 [95% CI 0.47-0.78], P<0.001). Differences in PFS2nd between study-arms were evident in patients with LPT, but not in patients with RPT (Cox model interaction test, P=0.12). Consistent observations were also made for OS2nd.

Conclusion: This retrospective analysis of FIRE-3 indicates that efficacy of second-line therapy was significantly greater in patients with left-sided tumors as compared to right-sided tumors. This difference was driven by superior activity of second-line regimens of the initial cetuximab-arm as compared to the initial bevacizumab-arm in left-sided tumors. Our observations confirm the strong prognostic value of primary tumor location in second-line therapy of mCRC.

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