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Clinical Studies

Chemotherapy (doublet or triplet) plus targeted therapy by RAS status as conversion therapy in colorectal cancer patients with initially unresectable liver-only metastases. The UNICANCER PRODIGE-14 randomised clinical trial

British Journal of Cancer volume 126, pages 1264–1270 (2022)Cite this article

Subjects

Abstract

Background

Colorectal cancer (CRC) patients have a better prognosis if metastases are resectable. Initially, unresectable liver-only metastases can be converted to resectable with chemotherapy plus a targeted therapy. We assessed which of chemotherapy doublet (2-CTx) or triplet (3-CTx), combined with targeted therapy by RAS status, would be better in this setting.

Methods

PRODIGE 14 was an open-label, multicenter, randomised Phase 2 trial. CRC patients with initially defined unresectable liver-only metastases received either, 2-CTx (FOLFOX or FOLFIRI) or 3-CTx (FOLFIRINOX), plus bevacizumab/cetuximab by RAS status. The primary endpoint was to increase the R0/R1 liver-resection rate from 50 to 70% with the 3-CTx.

Results

Patients (n = 256) were mainly men with an ECOG PS of 0, and a median age of 60 years. In total, 109 patients (42.6%) had RAS-mutated tumours. After a median follow-up of 45.6 months, the R0/R1 liver-resection rate was 56.9% (95% CI: 48–66) with the 3-CTx versus 48.4% (95% CI: 39–57) with the 2-CTx (P = 0.17). Median overall survival was 43.4 months with 3-CTx versus 40 months with 2-CTx.

Conclusion

We failed to increase from 50 to 70% the R0/R1 liver-resection rate with the use of 3-CTx combined with bevacizumab or cetuximab by RAS status in CRC patients with initially unresectable liver metastases.

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Fig. 1
Fig. 2: Survival times in the intent-to-treat populations.

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Data availability

Unicancer will share de-identified individual data that underlie the results reported under the following conditions: the data shared will be limited to that required for independent mandated verification of the published results, the reviewer will need authorisation from Unicancer for personal access, and data will only be transferred after signing of a data access agreement. A decision concerning the sharing of other study documents, including protocol and statistical analysis plan, will be examined upon request. Unicancer will consider access to study data upon written detailed request sent to l-monard@unicancer.fr, from 6 months until 5 years after the publication of this article.

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Acknowledgements

We thank the patients and their families for participating in the study. Also, we would like to thank Trevor Stanbury (UNICANCER) for medical writing support. We are also indebted to all the participating centers and to The Ligue Nationale Contre le Cancer. This trial was made possible through an unrestricted grant from Merck-Serono France.

Funding

This trial was made possible through an unrestricted grant from Merck-Serono France. Investigators list: INVESTIGATOR NAME: SITE, CITY. Pr. Marc YCHOU: Institut Régional du Cancer de Montpellier/Val d’Aurelle (ICM), Montpellier; Dr. Laurent MINEUR: Institut Ste Catherine, Avignon; Pr. Olivier BOUCHE: CHU de Reims, Reims; Dr. Pascale MARIANI: Institut Curie, Paris; Dr. Kartine BOUHIER-LEPORIER: CHU Côte de Nacre, Caen; Dr. Marianne FONCK: Institut Bergonié, Bordeaux; Dr. Roger FAROUX: CHD Vendée, La Roche sur Yon; Dr. Alice GAGNAIRE: CHU Dijon - Hôpital Du Bocage, Dijon; Dr. Eric FRANCOIS: Centre Antoine Lacassagne, Nice; Dr. Julien FORESTIER: Hôpital Edouard Herriot, Lyon; Pr François GHIRINGHELLI: Centre G. F. Leclerc, Dijon; Dr. Driffa MOUSSATA: Centre hospitalier Lyon Sud, Pierre-Benite; Dr. Gaël DEPLANQUE: Centre Hospitalier Saint-Joseph, Paris; Dr. Jean-Louis LEGOUX: CHR d’Orléans - La Source, Orleans; Dr. Cédric LECAILLE: Polyclinique de Bordeaux Nord Aquitaine, Bordeaux; Pr. Nicole TUBIANA-MATHIEU: CHU Dupuytren, Limoges; Mr. Michel RIVOIRE: Centre Léon Bérard, Lyon; Dr. Marie-Pierre GALAIS: Centre François Baclesse, Caen; Pr. Rosine GUIMBAUD: Centre hospitalier Rangueil, Toulouse; Dr. Francine FEIN: CHU Jean Minjoz, Besancon; Dr. Philippe HOUYAU: Clinique Claude Bernard, Albi; Pr. Thomas APARICIO: Hôpital Avicenne, Bobigny; Pr. Jean-François SEITZ: CHU La Timone, Marseille; Dr. Stephen ELLIS: Centre Catalan d’oncologie, Perpignan; Dr. Stéphane REMY: Centre d’oncologie et de radiothérapie du Pays basque, Bayonne; Dr. Faiza KHEMISSA - AKOUZ: Hôpital Saint Jean, Perpignan; Dr. Mohammed RAMDANI: Centre Hospitalier de Béziers, Béziers; Dr. Anne MERCIER - BLAS: CHP Saint Grégoire, Saint Gregoire; Pr. Eric ASSENAT: CHU Saint Eloi - CHRU de Montpellier, Montpellier; Pr. Julien TAIEB: Hôpital Européen Georges Pompidou, Paris; Pr. René ADAM: Hôpital Paul Brousse, Villejuif; Dr. Hervé PERRIER: Hôpital St Joseph, Marseille; Dr. Agnès PELAQUIER: Centre hospitalier Montelimar, Montelimar; Pr. Emmanuel MITRY: Hôpital Huguenin - Institut Curie, Saint-Cloud; Dr. Serge FRATTE: CHBM - Site du Mittan, Montbeliard; Dr. Franck AUDEMAR: Centre hospitalier Côte Basque, Bayonne; Dr. Jean-Luc LABOUREY: Centre hospitalier de Carcassonne, Carcassone; Dr. Mathilde MARTINEZ: Clinique Pasteur, Toulouse; Dr. Christian BOREL: Centre Paul Strauss, Strasbourg; Dr. Etienne SUC: Clinique St Jean du Languedoc, Toulouse; Dr. Christine LE FOLL: Centre hospitalier Marne la Vallée, Jossigny; Dr. Etienne MAURIAC: Polyclinique Côte Basque Sud, Saint Jean de Luz; Dr. Denis PÈRE-VERGĒ: Centre Hospitalier Saint-Joseph-Saint-Luc, Lyon.

Author information

Authors and Affiliations

  1. Department of Digestive Oncology, Institut du Cancer de Montpellier, Montpellier, France

    Marc Ychou & Antoine Adenis

  2. Department of Surgical Oncology, Léon Bérard Cancer Center, Lyon, France

    Michel Rivoire

  3. Biometrics Unit, Institut du Cancer de Montpellier, Montpellier, France

    Simon Thezenas

  4. Department of Digestive Oncology - IUCT Rangueil-Larrey, CHU de Toulouse, Toulouse, France

    Rosine Guimbaud

  5. Department of Medical Oncology, Centre Georges François Leclerc, Dijon, France

    Francois Ghiringhelli

  6. Department of Medical Oncology, Centre Hospitalier Privé de Saint-Grégoire, Saint-Grégoire, France

    Anne Mercier-Blas

  7. Department of Digestive Oncology, Institut Sainte Catherine, Avignon, France

    Laurent Mineur

  8. Department of Medical Oncology, Centre Antoine Lacassagne, Nice, France

    Eric Francois

  9. Gastroenterology unit, Centre Hospitalier Saint-Jean, Perpignan, France

    Faiza Khemissa

  10. Department of Hepato-gastroenterology and Digestive Oncology, Hôpital Lyon Sud, Lyon, France

    Marion Chauvenet

  11. Department of Digestive and Endocrine Surgery, Hôpital Robert Debré, Reims, France

    Reza Kianmanesh

  12. Department of Digestive Oncology, Institut Bergonié, Bordeaux, France

    Marianne Fonck

  13. Department of Medical Oncology, Clinique Claude Bernard, Albi, France

    Philippe Houyau

  14. Department of Gastroenterology and Digestive Oncology, Hôpital Saint Louis, APHP, Paris, France

    Thomas Aparicio

  15. Department of Medical Oncology, Centre François Baclesse, Caen, France

    Marie-Pierre Galais

  16. Gastroenterology unit, Centre hospitalier Côte Basque, Bayonne, France

    Franck Audemar

  17. Department of Digestive Oncology, CHU Saint Eloi, Montpellier, France

    Eric Assenat

  18. Translational Research Unit, Institut du Cancer de Montpellier, Montpellier, France and IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Montpellier, France

    Evelyne Lopez-Crapez

  19. R&D Unicancer, Paris, France

    Claire Jouffroy

  20. Hepatobiliary Centre, Paul Brousse Hospital, AP-HP, Villejuif, France

    René Adam

  21. Department of Hepatogastroenterology and Digestive Oncology, Hôpital Robert Debré, Reims, France

    Olivier Bouché

Authors
  1. Marc Ychou
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  2. Michel Rivoire
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  3. Simon Thezenas
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  4. Rosine Guimbaud
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  5. Francois Ghiringhelli
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  6. Anne Mercier-Blas
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  7. Laurent Mineur
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  8. Eric Francois
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  9. Faiza Khemissa
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  10. Marion Chauvenet
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  11. Reza Kianmanesh
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  12. Marianne Fonck
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  13. Philippe Houyau
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  14. Thomas Aparicio
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  15. Marie-Pierre Galais
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  16. Franck Audemar
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  17. Eric Assenat
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  18. Evelyne Lopez-Crapez
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  19. Claire Jouffroy
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  20. Antoine Adenis
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  21. René Adam
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  22. Olivier Bouché
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Contributions

Dr. MY had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: MY, RA, OB and MR. Acquisition, analysis or interpretation of the data: MY, AA and ST. Drafting of the manuscript: AA, EL-C, ST and MY. Critical revision of the manuscript for important intellectual content: all the authors. Statistical analysis: Thezenas. Administrative, technical or material support: MY, MR, RG, FG, EL-C, AM-B, LM, EF, FK, MC, RK, MF, PH, TA, M-PG, FA, EA, CJ, AA and OB; supervision: MY.

Corresponding author

Correspondence to Marc Ychou.

Ethics declarations

Ethics approval and consent to participate

The study complied with the Declaration of Helsinki, good clinical practice guidelines, and other local laws. The study documents were approved by a French ethics committee, “Comité de Protection des Personnes Sud Méditerranée IV”. Patients provided written informed consent before enrolment.

Consent to publish

Not applicable.

Competing interests

MY reported receiving honoraria from Amgen, Bayer, Merck, Roche, and Servier. MR has nothing to disclose. ST has nothing to disclose. RG reported personal fees from AAA, Amgen, Astra-Zeneca, BMS, P. Fabre, Novartis, Roche, Servier, outside the submitted work. FG served on external advisory boards for Roche; research funding from Roche, Genentech, Amgen, Enterome, Servier; received funding for a clinical trial from Astra-Zeneca, received fee for communication by Amgen, Astra-Zeneca, BMS, Sanofi, Merck-Serono, Servier and received fee for travel by Roche and Servier. AM-B has nothing to disclose. LM has nothing to disclose. EF reported personal fees from ROCHE, personal fees from SERVIER, personal fees from NOVARTIS, personal fees from MSD, outside the submitted work. FK reported personal feed from Sanofi, other fees from Roche (congress support), other fees from Ipsen (congress support), outside the submitted work. MC has nothing to disclose. RK has nothing to disclose. MF has nothing to disclose. PH has nothing to disclose. TA reported personal fees from Roche, personal fees from Servier, personal fees from Amgen, personal fees from Ipsen, personal fees from Sanofi, non-financial support from Bayer, outside the submitted work. M-PG reported other relevant financial interest from Roche (travel), other relevant financial interest from Amgen (travel, board), outside the submitted work. FA reported personal fees from Sanofi, personal fees from Merck, personal fees from Amgen, personal fees from Servier, personal fees from Roche, outside the submitted work. EA reported other fees (advisory board) from Roche, from Astrazeneca, from Ipsen, from Bayer, from Sanofi, from AMGEN, from AAA, outside the submitted work. EL-C has nothing to disclose, CJ has nothing to disclose. AA reported receiving honoraria from Bayer, Bristol-Myers Squibb, Merck-Sharp Dohme, Sanofi, and Servier. RA reported personal fees from Merck (congress presentation), personal fees from Sanofi (congress presentation), outside the submitted work. OB reported personal fees from ROCHE (self honoraria, advisory/consultancy), personal fees from AMGEN (self honoraria, speaker bureau/expert testimony), personal fees from MERCK KGaA (self honoraria, advisory/consultancy), personal fees from SERVIER (self honoraria, speaker bureau/expert testimony), personal fees from BAYER (self honoraria, advisory/consultancy), personal fees from PIERRE FABRE (self honoraria, speaker bureau/expert testimony), personal fees from Astra-Zeneca (self honoraria, advisory/consultancy), personal fees from Grunenthal (self honoraria, advisory/consultancy), personal fees from MSD (Self honoraria, advisory/consultancy), non-financial support from Roche (travel/accommodation/expenses) and non-financial support from Servier (travel/accommodation/expenses) outside the submitted work.

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Ychou, M., Rivoire, M., Thezenas, S. et al. Chemotherapy (doublet or triplet) plus targeted therapy by RAS status as conversion therapy in colorectal cancer patients with initially unresectable liver-only metastases. The UNICANCER PRODIGE-14 randomised clinical trial. Br J Cancer 126, 1264–1270 (2022). https://doi.org/10.1038/s41416-021-01644-y

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