Response to the Letter to the Editor “Pancreatic Cancer and FOLFIRINOX: Should We Resect All Responders?” by Neoptolemos and Colleagues

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Reply:
We thank Prof Neoptolemos and colleagues for their interest in our work1 and the comments that put our work in the context of the current status and the developments of neaoadjuvant and adjuvant therapy in pancreatic cancer. Regarding the question on the number of patients who were not initially seen in our center, this is not expected to cause a relevant bias, as the therapy was performed in a similar fashion in the referring centers and the FOLFIRINOX protocol did not differ. Furthermore, once the patients presented in Heidelberg, the initial imaging before neoadjuvant treatment was reviewed and the criteria for unresecability were defined retrospectively with the results that are given in our publication (ie, vascular infiltration or metastases). Patients, who had undergone neoadjuvant therapy elsewhere for borderline resectability or even resectable disease, were not included in the presented collective. We certainly agree that all retrospective studies are subjected to a selection bias and it would be desirable to evaluate the different approaches of neoadjuvant treatment in a prospective and randomized controlled setting. Currently, amongst others, the European study group for pancreatic cancer (ESPAC) group has undertaken these efforts with regard to the improvement of adjuvant therapy and achieved an important step with the completion of the ESPAC-4 trial, showing the efficacy of a combined adjuvant treatment by gemcitabine and capecitabine.2 The neoadjuvant protocols are under investigation within the ESPAC-5 study3 and the efforts are ongoing to improve evidence for this field. To date, we still face the challenge of pancreatic ductal adenocarcinoma (PDAC) patient selection for the optimal treatment in this devastating disease.4 As pointed out by Neoptolemos and colleagues, we still fail in this respect and the great aim of precision oncology has not yet been achieved. With regard to neoadjuvant FOLFIRINOX treatment, we believe that in locally advanced PDAC the selection should currently not be based on any markers. The markers that are available today show a poor accuracy and—as demonstrated in our study—especially CA19-9 was not helpful for selection. In contrast, we think that the clinical performance status of the patient must be the major criterion for decision and FOLFIRINOX should be chosen whenever possible. Furthermore, the problem of response evaluation is unsolved in PDAC. As shown by Ferrone et al,5 radiographic examination does not reflect response adequately, which is in concordance with our experience. Consequently, we should resect not only the “responders” with a tumor downsizing. We strongly believe that all “nonprogressors” showing a stable imaging finding during restaging should undergo a surgical exploration and resection whenever possible. The vitality of tumor-suspicious tissue findings can only be confirmed or ruled out during surgery. Not to explore these patients surgically would automatically result in a palliative therapy, which is clearly inferior to the combination of resection and adjuvant chemotherapy after pretreatment with FOLFIRINOX. Therefore, although we still face “nonprecision” treatment conditions, a maximum effect can be achieved by this multimodal approach and represents the best option until more progress is made and a better patient stratification is possible.

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