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Histopathologic Regression and Survival in RAS Wildtype Metastatic Colorectal Cancer Under First-Line Treatment – Subgroup Analysis of the VOLFI Trial (AIO-KRK-0109)

Received: 24 June 2021    Accepted: 12 July 2021    Published: 27 July 2021
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Abstract

Aim: The VOLFI trial demonstrated an improved objective response rate through the addition of panitumumab to FOLFOXIRI in untreated all-RAS-wildtype mCRCs compared to FOLFOXIRI alone. In this subgroup analysis, we focused on histopathological response as a predictive marker for PFS. Additionally, we analyzed chemotherapy induced steatosis hepatitis (CASH) in both treatment arms. Methods: Histopathological response, CASH, sinusoidal obstructive syndrome, ballooning, steatosis, cholestasis, fibrosis and inflammation were determined in 14 resected liver metastasis. PFS was estimated using Kaplan-Meier method, the logrank test was used for the statistical comparison. The trial is registered with Clinical Trials. gov, NCT01328171. Results: Tissue of 14/18 resected pts. was evaluable. Median age was 57.5 yrs. (32–67), 7 male and 7 females. All primary tumors were located in the left colon. Molecular analysis detected one BRAF V600E mutation and one MSI-H tumor. Median treatment duration until resection were 7 cycles (3 – 12) panitumumab/mFOLFOXIRI and 9.5 cycles (7 - 11) FOLFOXIRI. 7 pts. achieved very good histopathological response corresponding to ≤20% vital tumor cells (panitumumab/ mFOLFOXIRI vs. FOLFOXIRI 2/5) and 7 pts. showed vital tumor cells >20% (panitumumab/mFOLFOXIRI vs. FOLFOXIRI 2/5). A very good histopathological response (residual tumor cells in proportion to the total tumor area ≤20%) showed a trend to an improved PFS in comparison to >20% (median PFS 12.40; 95% CI 6.43-51.22 vs. PFS 9.88; 95% CI 6.17-15.26 months). The severity of CASH was not increased by the addition of panitumumab or longer duration of chemotherapy. Discussion: In this analysis histopathological response seems to correlate with a better PFS after secondary metastasis resection. By analysis of liver toxicity, no relevant difference of CASH were detectable regarding panitumumab/mFOLFOXIRI vs. FOLFOXIRI or the duration of chemotherapy.

Published in International Journal of Clinical Oncology and Cancer Research (Volume 6, Issue 3)
DOI 10.11648/j.ijcocr.20210603.15
Page(s) 130-135
Creative Commons

This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited.

Copyright

Copyright © The Author(s), 2021. Published by Science Publishing Group

Keywords

Metastatic Colorectal Cancer, Regression Rate, Panitumumab, RAS, CASH

References
[1] Cremolini C, Loupakis F, Antoniotti C, Lonardi S. Early tumor shrinkage and depth of response predict long-term outcome in metastatic colorectal cancer patients treated with first-line chemotherapy plus bevacizumab: results from phase III TRIBE trial by the Gruppo Oncologico del Nord Ovest. Ann Oncol. 2015 Jun; 26 (6): 1188-94.
[2] Stintzing S, Modest DP, Rossius L et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer (FIRE-3): a post-hoc analysis of tumour dynamics in the final RAS wild-type subgroup of this randomised open-label phase 3 trial. Lancet Oncol. 2016 Oct; 17 (10): 1426-1434. doi: 10.1016/S1470-2045(16)30269-8. Epub 2016 Aug 27. Erratum in: Lancet Oncol. 2016 Oct; 17 (10): e420. Erratum in: Lancet Oncol. 2016 Nov; 17 (11): e479. PMID: 27575024.
[3] Moretto R, Rossini D, Zucchelli G, et al. Oligometastatic colorectal cancer: prognosis, role of locoregional treatments and impact of first-line chemotherapy-a pooled analysis of TRIBE and TRIBE2 studies by Gruppo Oncologico del Nord Ovest. Eur J Cancer. 2020 Nov; 139: 81-89. doi: 10.1016/j.ejca.2020.08.009. Epub 2020 Sep 23. PMID: 32979645.
[4] Modest DP, Martens UM, Riera-Knorrenschild J, et al. FOLFOXIRI Plus Panitumumab As First-Line Treatment of RAS Wild-Type Metastatic Colorectal Cancer: The Randomized, Open-Label, Phase II VOLFI Study (AIO KRK0109). J Clin Oncol. 2019; 37 (35): 3401–3411. doi: 10.1200/JCO.19.01340.
[5] Duwe G, Knitter S, Pesthy S, et al. Hepatotoxicity following systemic therapy for colorectal liver metastases and the impact of chemotherapy-associated liver injury on outcomes after curative liver resection. Eur J Surg Oncol. 2017; 43 (9): 1668–1681. doi: 10.1016/j.ejso.2017.05.008.
[6] Morris-Stiff, G, Tan, Y-M, Vauthey JN, et al. Hepatic complications following preoperative chemotherapy with oxaliplatin or irinotecan for hepatic colorectal metastases. Eur J Surg Oncol. 2008 Jun; 34 (6): 609-14. Epub 2007 Aug 30.
[7] Viganò L, Capussotti L, De Rosa G, De Saussure WO, Mentha G, Rubbia-Brandt L. Liver resection for colorectal metastases after chemotherapy: impact of chemotherapy-related liver injuries, pathological tumor response, and micrometastases on long-term survival. Ann Surg 2013; 258: 731-40; discussion 741- 2 [PMID: 24045448 DOI: 10.1097/SLA.0b013e3182a6183e].
[8] Pandey P, Pandey A, Dillhoff M, et al., Assessing the Non-tumorous Liver: Implications for Patient Management and Surgical Therapy. J Gastrointest Surg. 2018 Feb; 22 (2): 344-360. doi: 10.1007/s11605-017-3562-3. Epub 2017 Sep 18.
[9] Zhao J, van Mierlo KMC, Gómez-Ramírez J, et al. Systematic review of the influence of chemotherapy-associated liver injury on outcome after partial hepatectomy for colorectal liver metastases. Br J Surg. 2017; 104 (8): 990–1002. doi: 10.1002/bjs.10572.
[10] Pilgrim CH, Thomson BN, Banting S, Phillips WA, Michael M. The developing clinical problem of chemotherapy-induced hepatic injury. ANZ J Surg 2012; 82 (1e2): 23–9.
[11] Rubbia-Brandt L, Audard V, Sartoretti P, et al. Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Ann Oncol 2004; 15 (3): 460–6.
[12] Grigorian A and O'Brien CB. Hepatotoxicity Secondary to Chemotherapy. J Clin Transl Hepatol. 2014 Jun; 2 (2): 95–102. Published online 2014 Jun 15. doi: 10.14218/JCTH.2014.00011.
[13] Moreno Prats M, Sasatomi E, Stevenson HL. Colorectal Liver Metastases: A Pathologist's Guide to Creating an Informative Report and Improving Patient Care. Arch Pathol Lab Med. 2019 Feb; 143 (2): 251-257. doi: 10.5858/arpa.2017-0505-RA. Epub 2018 May 23. PMID: 29790787.
[14] Keating GM. Panitumumab: a review of its use in metastatic colorectal cancer. Drugs. 2010 May 28; 70 (8): 1059-78. doi: 10.2165/11205090-000000000-00000.
[15] Blazer III DG, Kishi Y, Dipen MM et al., Pathologic Response to Preoperative Chemotherapy: A New Outcome End Point After Resection of Hepatic Colorectal Metastases. J Clin Oncol 2008, 25: 5344-5351; DOI: 10.1200/JCO.2008.17.5299.
[16] Van der Bol JM, Mathijssen RHJ, Creemers GJM, Planting AST, Loos WJ, Wiemer EAC, et al. A CYP3A4 phenotype-based dosing algorithm for individ-ualized treatment of irinotecan. Clin Cancer Res Off J Am Assoc Cancer Res2010; 16 (2): 736–42.
[17] Meunier L and Larrey D. Chemotherapy-associated steatohepatitis. Ann Hepatol. 2020 Jan 30. pii: S1665-2681(20)30004-1. doi: 10.1016/j.aohep.2019.11.012.
[18] Schmiegel W, Buchberger B, Follmann M et al. (2017) Z Gastroenterol 55: 1344-1498.
[19] Robinson SM, Wilson CH, Burt AD, et al. Chemotherapy-associated liver injury in patients with colorectal liver metastases: a systematic review and meta-analysis. Ann Surg Oncol 2012; 19 (13): 4287–99.
[20] Kishi Y, Zorzi D, Contreras CM, Maru DM, Kopetz S, Ribero D, Motta M, Ravarino N, Risio M, Curley SA, Abdalla EK, Capussotti L, Vauthey JN. Extended preoperative chemotherapy does not improve pathologic response and increases postoperative liver insufficiency after hepatic resection for colorectal liver metastases. Ann Surg Oncol 2010; 17: 2870-2876 [PMID: 20567921 DOI: 10.1245/s10434-010-1166-1].
[21] Rubbia-Brandt L, Giostra E, Brezault C et al., Importance of histological tumor response assessment in predicting the outcome in patients with colorectal liver metastases treated with neo-adjuvant chemotherapy followed by liver surgery. Ann Oncol. 2007 Feb; 18 (2): 299-304. Epub 2006 Oct 23.
[22] Zhang Y, Jiang HY, Wei Y, Song B. Sinusoidal obstruction syndrome: A systematic review of etiologies, clinical symptoms, and magnetic resonance imaging features. World J Clin Cases. 2019 Sep 26; 7 (18): 2746-2759. doi: 10.12998/wjcc.v7.i18.2746.
[23] Zhang Y, Yan Y, Song B. Noninvasive imaging diagnosis of sinusoidal obstruction syndrome: a pictorial review. Insights Imaging. 2019 Nov 20; 10 (1): 110. doi: 10.1186/s13244-019-0791-x.
Cite This Article
  • APA Style

    Stefanie Noepel-Duennebacke, Henrik Juette, Celine Lugnier, Dominik Paul Modest, Uwe Martens, et al. (2021). Histopathologic Regression and Survival in RAS Wildtype Metastatic Colorectal Cancer Under First-Line Treatment – Subgroup Analysis of the VOLFI Trial (AIO-KRK-0109). International Journal of Clinical Oncology and Cancer Research, 6(3), 130-135. https://doi.org/10.11648/j.ijcocr.20210603.15

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    ACS Style

    Stefanie Noepel-Duennebacke; Henrik Juette; Celine Lugnier; Dominik Paul Modest; Uwe Martens, et al. Histopathologic Regression and Survival in RAS Wildtype Metastatic Colorectal Cancer Under First-Line Treatment – Subgroup Analysis of the VOLFI Trial (AIO-KRK-0109). Int. J. Clin. Oncol. Cancer Res. 2021, 6(3), 130-135. doi: 10.11648/j.ijcocr.20210603.15

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    AMA Style

    Stefanie Noepel-Duennebacke, Henrik Juette, Celine Lugnier, Dominik Paul Modest, Uwe Martens, et al. Histopathologic Regression and Survival in RAS Wildtype Metastatic Colorectal Cancer Under First-Line Treatment – Subgroup Analysis of the VOLFI Trial (AIO-KRK-0109). Int J Clin Oncol Cancer Res. 2021;6(3):130-135. doi: 10.11648/j.ijcocr.20210603.15

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  • @article{10.11648/j.ijcocr.20210603.15,
      author = {Stefanie Noepel-Duennebacke and Henrik Juette and Celine Lugnier and Dominik Paul Modest and Uwe Martens and Renate Klaassen-Mielke and Volker Heinemann and Thomas Seufferlein and Michael Geissler and Andrea Tannapfel and Anke Reinacher-Schick and Iris Tischoff},
      title = {Histopathologic Regression and Survival in RAS Wildtype Metastatic Colorectal Cancer Under First-Line Treatment – Subgroup Analysis of the VOLFI Trial (AIO-KRK-0109)},
      journal = {International Journal of Clinical Oncology and Cancer Research},
      volume = {6},
      number = {3},
      pages = {130-135},
      doi = {10.11648/j.ijcocr.20210603.15},
      url = {https://doi.org/10.11648/j.ijcocr.20210603.15},
      eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.ijcocr.20210603.15},
      abstract = {Aim: The VOLFI trial demonstrated an improved objective response rate through the addition of panitumumab to FOLFOXIRI in untreated all-RAS-wildtype mCRCs compared to FOLFOXIRI alone. In this subgroup analysis, we focused on histopathological response as a predictive marker for PFS. Additionally, we analyzed chemotherapy induced steatosis hepatitis (CASH) in both treatment arms. Methods: Histopathological response, CASH, sinusoidal obstructive syndrome, ballooning, steatosis, cholestasis, fibrosis and inflammation were determined in 14 resected liver metastasis. PFS was estimated using Kaplan-Meier method, the logrank test was used for the statistical comparison. The trial is registered with Clinical Trials. gov, NCT01328171. Results: Tissue of 14/18 resected pts. was evaluable. Median age was 57.5 yrs. (32–67), 7 male and 7 females. All primary tumors were located in the left colon. Molecular analysis detected one BRAF V600E mutation and one MSI-H tumor. Median treatment duration until resection were 7 cycles (3 – 12) panitumumab/mFOLFOXIRI and 9.5 cycles (7 - 11) FOLFOXIRI. 7 pts. achieved very good histopathological response corresponding to ≤20% vital tumor cells (panitumumab/ mFOLFOXIRI vs. FOLFOXIRI 2/5) and 7 pts. showed vital tumor cells >20% (panitumumab/mFOLFOXIRI vs. FOLFOXIRI 2/5). A very good histopathological response (residual tumor cells in proportion to the total tumor area ≤20%) showed a trend to an improved PFS in comparison to >20% (median PFS 12.40; 95% CI 6.43-51.22 vs. PFS 9.88; 95% CI 6.17-15.26 months). The severity of CASH was not increased by the addition of panitumumab or longer duration of chemotherapy. Discussion: In this analysis histopathological response seems to correlate with a better PFS after secondary metastasis resection. By analysis of liver toxicity, no relevant difference of CASH were detectable regarding panitumumab/mFOLFOXIRI vs. FOLFOXIRI or the duration of chemotherapy.},
     year = {2021}
    }
    

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  • TY  - JOUR
    T1  - Histopathologic Regression and Survival in RAS Wildtype Metastatic Colorectal Cancer Under First-Line Treatment – Subgroup Analysis of the VOLFI Trial (AIO-KRK-0109)
    AU  - Stefanie Noepel-Duennebacke
    AU  - Henrik Juette
    AU  - Celine Lugnier
    AU  - Dominik Paul Modest
    AU  - Uwe Martens
    AU  - Renate Klaassen-Mielke
    AU  - Volker Heinemann
    AU  - Thomas Seufferlein
    AU  - Michael Geissler
    AU  - Andrea Tannapfel
    AU  - Anke Reinacher-Schick
    AU  - Iris Tischoff
    Y1  - 2021/07/27
    PY  - 2021
    N1  - https://doi.org/10.11648/j.ijcocr.20210603.15
    DO  - 10.11648/j.ijcocr.20210603.15
    T2  - International Journal of Clinical Oncology and Cancer Research
    JF  - International Journal of Clinical Oncology and Cancer Research
    JO  - International Journal of Clinical Oncology and Cancer Research
    SP  - 130
    EP  - 135
    PB  - Science Publishing Group
    SN  - 2578-9511
    UR  - https://doi.org/10.11648/j.ijcocr.20210603.15
    AB  - Aim: The VOLFI trial demonstrated an improved objective response rate through the addition of panitumumab to FOLFOXIRI in untreated all-RAS-wildtype mCRCs compared to FOLFOXIRI alone. In this subgroup analysis, we focused on histopathological response as a predictive marker for PFS. Additionally, we analyzed chemotherapy induced steatosis hepatitis (CASH) in both treatment arms. Methods: Histopathological response, CASH, sinusoidal obstructive syndrome, ballooning, steatosis, cholestasis, fibrosis and inflammation were determined in 14 resected liver metastasis. PFS was estimated using Kaplan-Meier method, the logrank test was used for the statistical comparison. The trial is registered with Clinical Trials. gov, NCT01328171. Results: Tissue of 14/18 resected pts. was evaluable. Median age was 57.5 yrs. (32–67), 7 male and 7 females. All primary tumors were located in the left colon. Molecular analysis detected one BRAF V600E mutation and one MSI-H tumor. Median treatment duration until resection were 7 cycles (3 – 12) panitumumab/mFOLFOXIRI and 9.5 cycles (7 - 11) FOLFOXIRI. 7 pts. achieved very good histopathological response corresponding to ≤20% vital tumor cells (panitumumab/ mFOLFOXIRI vs. FOLFOXIRI 2/5) and 7 pts. showed vital tumor cells >20% (panitumumab/mFOLFOXIRI vs. FOLFOXIRI 2/5). A very good histopathological response (residual tumor cells in proportion to the total tumor area ≤20%) showed a trend to an improved PFS in comparison to >20% (median PFS 12.40; 95% CI 6.43-51.22 vs. PFS 9.88; 95% CI 6.17-15.26 months). The severity of CASH was not increased by the addition of panitumumab or longer duration of chemotherapy. Discussion: In this analysis histopathological response seems to correlate with a better PFS after secondary metastasis resection. By analysis of liver toxicity, no relevant difference of CASH were detectable regarding panitumumab/mFOLFOXIRI vs. FOLFOXIRI or the duration of chemotherapy.
    VL  - 6
    IS  - 3
    ER  - 

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Author Information
  • Department of Hematology, Oncology and Palliative Care, St. Josef-Hospital Bochum, Ruhr-University Bochum, Bochum, Germany

  • Institute of Pathology, Ruhr-University Bochum, Bochum, Germany

  • Department of Hematology, Oncology and Palliative Care, St. Josef-Hospital Bochum, Ruhr-University Bochum, Bochum, Germany

  • Department of Hematology, Oncology, and Tumorimmunology (CVK/CCM), University Medicine Charite, Berlin, Germany

  • Department of Medicine, SLK-Kliniken Heilbronn, Heilbronn, Germany

  • Department of Medical Informatics, Biometry and Epidemiology, Ruhr University Bochum, Bochum, Germany

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

  • Department of Medicine I, Hospital of the University, Ulm, Germany

  • Department of Hematology/Oncology, Clinic of Esslingen, Esslingen Germany

  • Institute of Pathology, Ruhr-University Bochum, Bochum, Germany

  • Department of Hematology, Oncology and Palliative Care, St. Josef-Hospital Bochum, Ruhr-University Bochum, Bochum, Germany

  • Institute of Pathology, Ruhr-University Bochum, Bochum, Germany

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