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Phase II multicentre study of efficacy and feasibility of dose-intensified preoperative weekly cisplatin, epirubicin, and paclitaxel (PET) in resectable gastroesophageal cancer

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Abstract

Background

Perioperative chemotherapy improves the overall survival of resectable gastroesophageal adenocarcinoma (GEA) patients. However, more than 40 % of the patients are not healthy enough to complete their post-operative chemotherapy, and the progression-free survival rate is lower than 35 % at 5 years. In order to optimise neoadjuvant chemotherapy regimen, a pilot study of weekly dose-intensified cisplatin, epirubicin, and paclitaxel (PET) was conducted. The primary objective was a complete resection (R0) rate. Then, a R0 rate ≤80 % was considered as uninteresting, with an expected R0 rate of 92 %. Secondary objectives were the feasibility, safety, histological response rate (Becker score), and survival (Trial registration: NCT01830270).

Methods

Patients with >T1N0M0 GEA were included. Treatment consisted of eight preoperative cycles of weekly PET regimen at 30/50/80 mg/m2 of cisplatin, epirubicin, and paclitaxel, respectively. Primary prophylaxis by granulocyte colony-stimulating factor was administered. Surgery was performed 4–6 weeks following the last cycle of chemotherapy. Using Fleming two-step design with a unilateral alpha type one error of 5 % and a statistical power of 80 %, it would be required to include 68 patients. At planned interim analysis for futility, it was required to observe at least 25 of 29 patients with R0 resection to pursue inclusion. At the second step, it was required to observe at least 61 of 68 patients with R0 resection to conclude for promising activity of the dose-intensified chemotherapy.

Results

Between May 2011 and January 2013, 29 patients were enrolled. Median age was 62 years (range 39–83 years), and seven (24 %) patients presented signet-ring cell histology. Twenty-seven (93 %) patients underwent surgery. Pathological complete responses (Becker score 1a) were observed in four patients, and nearly complete responses (Becker score 1b) for additional three patients. A R0 rate was achieved for 24 of 29 (82.7 %; 95 % CI 64–94 %) patients. No Becker score 1a/1b response was observed among patients with signet-ring cell GEA. Twenty-one (72 %) patients completed all eight cycles, and 86 % received seven or more cycles. Sixteen (56 %) patients experienced grade 3–4 neutropenia, and five patients had febrile neutropenia. Among non-haematological toxicities, mucositis and fatigue were the most frequent ones. The median-delivered relative dose intensity (DI) was 80 % for cisplatin, 75 % for epirubicin, and 79 % for paclitaxel. However, only 45 % of the patients received at least 80 % of the planned median DI for all three drugs.

Conclusions

Despite high R0 and pathological response rates, neoadjuvant PET chemotherapy did not meet the primary end-point and failed to show an acceptable relative DI. PET chemotherapy is not recommended in resectable GEA patients.

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Acknowledgments

This work was supported in part by a research grant from the region of Franche Comté. The authors would like to thank the investigators and their team. The authors would like to thank Guadalupe Tizon for English writing assistance.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Medical Oncology, University Hospital of Besançon, Besançon, France

    Marine Jary, Thierry Nguyen, Christophe Borg & Stefano Kim

  2. Clinical Investigational Center, CIC-Biotherapy-506, University Hospital of Besançon, Besançon, France

    Marine Jary, Marion Jacquin, Christophe Borg & Stefano Kim

  3. Department of Oncology, Georges-Francois Leclerc Cancer Center, Dijon, France

    Francois Ghiringhelli

  4. Department of Gastroenterology, University Hospital of Besançon, Besançon, France

    Francine Fein

  5. Department of Gastroenterology, Hospital of Vesoul, Vesoul, France

    Denis Cleau

  6. Department of Pharmacology, University Hospital of Besançon, Besançon, France

    Virginie Nerich

  7. EA 3181, University of Franche-Comté, Besançon, France

    Virginie Nerich, Séverine Valmary-Degano & Franck Bonnetain

  8. University of Franche-Comté, Besançon, France

    Maryame El Gani

  9. Department of Digestive Surgery and Liver Transplantation, University Hospital of Besançon, Besançon, France

    Pierre Mathieu

  10. Department of Pathology, University Hospital of Besançon, Besançon, France

    Séverine Valmary-Degano

  11. Department of Pathology, Georges-Francois Leclerc Cancer Center, Dijon, France

    Laurent Arnould

  12. Department of Pathology, Hospital of Belfort-Montbeliard, Belfort, France

    Catherine Lassabe

  13. Department of Surgery, Hospital of Belfort-Montbeliard, Montbeliard, France

    Najib Lamfichekh

  14. Department of Gastroenterology, Hospital of Belfort-Montbeliard, Belfort, France

    Serge Fratté

  15. Methodology and Quality of Life in Oncology Unit, University Hospital of Besançon, Besançon, France

    Sophie Paget-Bailly & Franck Bonnetain

  16. INSERM, Unit 1098, University of Franche-Comté, Besançon, France

    Christophe Borg

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  1. Marine Jary
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  2. Francois Ghiringhelli
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Correspondence to Stefano Kim.

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Jary, M., Ghiringhelli, F., Jacquin, M. et al. Phase II multicentre study of efficacy and feasibility of dose-intensified preoperative weekly cisplatin, epirubicin, and paclitaxel (PET) in resectable gastroesophageal cancer. Cancer Chemother Pharmacol 74, 141–150 (2014). https://doi.org/10.1007/s00280-014-2482-0

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