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Panitumumab as a radiosensitizing agent in KRAS wild-type locally advanced rectal cancer

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Abstract

Our goal was to optimize the radiosensitizing potential of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies, when given concomitantly with preoperative radiotherapy in KRAS wild-type locally advanced rectal cancer (LARC). Based on pre-clinical studies conducted by our group, we designed a phase II trial in which panitumumab (6 mg/kg/q2 weeks) was combined with preoperative radiotherapy (45 Gy in 25 fractions) to treat cT3-4/N + KRAS wild-type LARC. The primary endpoint was complete pathologic response (pCR) (H0 = 5 %, H1 = 17 %, α = 0.05, β = 0.2). From 19 enrolled patients, 17 (89 %) were evaluable for pathology assessment. Although no pCR was observed, seven patients (41 %) had grade 3 Dworak pathological tumor regression. The regimen was safe and was associated with 95 % of sphincter-preservation rate. No NRAS, BRAF, or PI3KCA mutation was found in this study, but one patient (5 %) showed loss of PTEN expression. The quantification of plasma EGFR ligands during treatment showed significant upregulation of plasma TGF-α and EGF following panitumumab administration (p < 0.05). At surgery, patients with important pathological regression (grade 3 Dworak) had higher plasma TGF-α (p = 0.03) but lower plasma EGF (p = 0.003) compared to those with grade 0–2 Dworak. Our study suggests that concomitant panitumumab and preoperative radiotherapy in KRAS wild-type LARC is feasible and results in some tumor regression. However, pCR rate remained modest. Given that the primary endpoint of our study was not reached, we remain unable to recommend the use of panitumumab as a radiosensitizer in KRAS wild-type LARC outside a research setting.

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Acknowledgments

We deeply acknowledge Jean-Luc Gala, Brigitte Honhon, Yannick Neybuch, Anne-France Dekairelle, Annelies Debucquoy, Aline Gillain, Fatima Hammouch, Janique Dewelle, Pierre Lefesvre, and Marie-Lise Vanderhaeghen for their contributions to this study. We also thank Amgen, Belgium. Finally, we thank Aileen Eiszele, BA (Hons), DipEd, GradDipBus, for editing this manuscript.

Funding

This study was supported by the Fonds de la Recherche Scientifique (FNRS, grant no. 7.4609.09), the Belgian “Plan National Cancer” (Action 29), and an unrestricted grant from Amgen, Belgium. Feby Mardjuadi is supported by the FNRS (Aspirant F.C. 81552). Karin Haustermans is a fundamental clinical researcher of the Research Foundation—Flanders, Belgium.

The preliminary results of this study have been published as an abstract at the American Society of Clinical Oncology 2012 meeting.

Conflicts of interest

Jean-Pascal Machiels received an unrestricted grant from Amgen, Belgium to support the phase II clinical trial. All remaining authors have declared no conflict of interest.

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Authors and Affiliations

  1. Institut de Recherche Expérimentale et Clinique, Pôle d’imagerie médicale, radiothérapie et oncologie (IREC/MIRO), Université catholique de Louvain, Brussels, Belgium

    Feby Ingriani Mardjuadi & Jean-Pascal Machiels

  2. Service d’oncologie médicale, Grand Hôpital de Charleroi (GhdC), Charleroi, Belgium

    Javier Carrasco & Jean-Luc Canon

  3. Service de gastroentérologie, Clinique St-Pierre, Ottignies, Belgium

    Jean-Charles Coche

  4. Service d’anatomie pathologie, Cliniques universitaires St-Luc, Brussels, Belgium

    Christine Sempoux & Anne Jouret-Mourin

  5. Clinique des Pathologies Tumorales du Colon et du Rectum, Centre du Cancer, Cliniques universitaires St-Luc, Brussels, Belgium

    Christine Sempoux, Anne Jouret-Mourin, Pierre Scalliet, Yves Humblet, Marc van den Eynde & Anne Moxhon

  6. Service d’oncologie médicale, Clinique et Maternité St-Elisabeth, Namur, Belgium

    Jean-Charles Goeminne & Peter Vuylsteke

  7. Service de radiothérapie, Clinique et Maternité St-Elisabeth, Namur, Belgium

    Jean-François Daisne

  8. Service d’oncologie, Hôpital de Jolimont, Haine-St-Paul, Belgium

    Thierry Delaunoit

  9. Service de radiothérapie, Hôpital St-Joseph, Gilly, Belgium

    Nicolas Meert

  10. Radiation Oncology, University Hospitals Leuven, Katholieke Universiteit Leuven, Leuven, Belgium

    Karin Haustermans

  11. Service d’oncologie médicale, Cliniques universitaires St-Luc, Avenue Hippocrate 10, 1200, Brussels, Belgium

    Feby Ingriani Mardjuadi, Yves Humblet, Marc van den Eynde, Anne Moxhon & Jean-Pascal Machiels

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  1. Feby Ingriani Mardjuadi
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Correspondence to Jean-Pascal Machiels.

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Mardjuadi, F.I., Carrasco, J., Coche, JC. et al. Panitumumab as a radiosensitizing agent in KRAS wild-type locally advanced rectal cancer. Targ Oncol 10, 375–383 (2015). https://doi.org/10.1007/s11523-014-0342-9

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