Reply to the letter to the editor ‘Anti-EGFR therapy in oesophagogastric cancer: precise but not enough’ by M. Salati and S. Cascinu
Authors: T. Ruhstaller, R. Langer, P. Thuss-Patience, W. Eisterer, M. Stahl
Journal: Annals of Oncology (2018)

Thank you very much for the possibility to reply to the letter of Salati and Cascinu who point to a very relevant fact in the field of EGFR targeting in the treatment of oesophageal cancer [1.Salati M. Cascinu S. Anti-EGFR therapy in oesophagogastric cancer: precise but not enough.Ann Oncol. 2018; 29: 1884-1885Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar]. We completely agree that, despite solid molecular background, the results of published studies did not fulfil the expectations. However, the REAL-3 and EXPAND trials, that were cited by the authors, added EGFR-inhibitors to different chemotherapy regimens in patients with metastatic disease. In the SCOPE-1 and the RTOG 0436 trials, cetuximab was added to definitive chemoradiation in mainly unresectable, locally advanced oesophageal carcinoma of both histologic subtypes. Our trial was the first one investigating multimodal therapy including surgery in patients with resectable tumours and therefore in less extended disease [2.Ruhstaller T. Thuss-Patience P. Hayoz S. et al.Neoadjuvant chemotherapy followed by chemoradiation and surgery with and without cetuximab in patients with resectable esophageal cancer: a randomized, open-label, phase III trial (SAKK 75/08).Ann Oncol. 2018; 29: 1386Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar]. It was designed in 2006/07 when the multimodal treatment of locally advanced oesophageal carcinomas consisted of conventional chemoradiation and/or surgery, a plateau in the efficacy had been reached and more than half of all patients died within 5 years due to tumour progression. At that time, emerging possibilities to use antagonists of growth factor signal transduction pathways were published in different tumour types. Bonner et al. showed that the addition of cetuximab to radiotherapy in treatment of stage III and IV non-metastatic squamous cell cancer of the head and neck improved local control and overall survival [3.Bonner J.A. Harari P.M. Giralt J. et al.Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck.N Engl J Med. 2006; 354: 567-578Crossref PubMed Scopus (4176) Google Scholar]. In a preceding phase I–II of SAKK the feasibility and safety of the addition of cetuximab to a trimodal treatment in locally advanced oesophageal cancer was tested [4.Ruhstaller T. Pless M. Dietrich D. et al.Cetuximab in combination with chemoradiotherapy before surgery in patients with resectable, locally advanced esophageal carcinoma: a prospective, multicenter phase IB/II Trial (SAKK 75/06).J Clin Oncol. 2011; 29: 626-631Crossref PubMed Scopus (100) Google Scholar]. In the SAKK 75/08 phase III trial, we could show that the addition of cetuximab led to a significant difference in loco-regional failure in a molecularly unselected population, probably due to a radiosensitizing effect, and a relevant improvement of overall survival. Obviously, loco-regional control can make an impact on survival particularly in resectable rather than more advanced disease. Combined with the existing evidence of missing systemic effect of cetuximab in more advanced disease, it seems that the window of opportunity for an intensified, neoadjvuant chemoradiation with the addition of cetuximab is limited to locally advanced, but still resectable disease where loco-regional relapses are frequent and have a relevant impact on overall survival. This suggests that our treatment strategies should be more differentiated according to the stage of the disease similar to other tumour types. However, in addition to the loco-regionally enhancing effect of cetuximab in combination with radiotherapy in the whole investigated population, there may also be a selected subgroup of patients with additional systemic benefit from anti-EGFR therapy as proposed by Salati and Cascinu. Elevated EGFR copy numbers in tumours, for example, have been described to be associated with response to EGFR-directed treatment [5.Petty R.D. Dahle-Smith A. Stevenson D.A.J. et al.Gefitinib and EGFR gene copy number aberrations in esophageal cancer.J Clin Oncol. 2017; 35: 2279-2287Crossref PubMed Scopus (79) Google Scholar]. In fact, our group is currently performing a comprehensive molecular analysis of the pretherapeutic biopsy material of the SAKK 75/08 trial in order to identify molecular signatures that would allow to better tailor EGFR targeting treatment in oesophageal cancers. None declared.