Reply: 'Comments on Stromal disrupting effects of nab-paclitaxel in pancreatic cancer'.

Sir,

In response to Boeck et al

We read with interest the comments made by Boeck about our study. We appreciate their attention to the units used to report CA19.9 levels, which indeed should have been U ml−1 and not U dl−1 as stated. We certainly agree that a high level of CA19.9 at diagnosis may be an indication of advanced disease and that this should be considered in the selection criteria in preoperative studies. Indeed in our study, with small sample size, one patient with very high CA19.9 level who actually progressed during chemotherapy skewed that average level of CA19.9. This patient was not operated and therefore does not affect the tissue results. As Boeck et al mention, levels of CA19.9 should be either a selection criteria or a stratification factor in outcome-oriented preoperative studies that should also include better imaging methods to determine responses and histological, rather than cytological, diagnosis. In our study, however, as the goals were to determine the effects of Nab-paclitaxel in tumour tissue, this criterion was not part of the eligibility criteria. We agree, however, that future controlled studies to confirm our observations should exclude patients with elevated CA19.9 and plan to do so.

In clinical practice, however, one of the goals of preoperative treatment is to identify patients with more advanced or resistant disease who can be spared from surgery, as surgery would not be beneficial for those patients. Thus, for patients with resectable or borderline resectable disease by CT scan and high (>180 U ml−1) CA19.9, we usually administer chemotherapy upfront and explore surgically those patients who do not progress after two cycles of treatment provided laparoscopic assessment of peritoneal disease is negative as well.

In response to Ramirez et al

We read with great interest the comments made by Ramírez in which they highlight the importance of tumour stroma in pancreatic cancer (PDAC) and the role of ‘pancreatic stellate cells' in the development of tumour stroma. The current data, while with still some inconsistencies, show that in preclinical models of PDAC, the combination of gemcitabine and Nab-paclitaxel (PTX) increases the delivery of gemcitabine to the tumour. Mechanistically, this has been explained by a decrease in the expression of the gemcitabine catabolism enzyme cytidine deaminase and hence increasing the intracellular retention time of the active gemcitabine metabolites or by elimination of the PDAC stroma (Von Hoff ; Frese ). In the only clinical study available so far, we have shown that Nab-PTX markedly alters the PDAC stroma and decreases the number of CAF (Alvarez ).

The precise mechanisms underlying these observations remain obscure. Selective binding of albumin-coated Nab-PTX to SPARC-positive cells or uptake of nutrient-rich drug by cancer cells by pynocitosis have been proposed and are the subject of specific studies. The role of SPARC has been studied in the MPACT randomised clinical trial and we hope to have these results available in the near future (Von Hoff ). As these authors propose, the effects of Nab-PTX on cancer stroma could be a consequence of the direct elimination of cancer cells and interruption of the cancer cell–stroma interactions. Certainly, additional preclinical and translational clinical studies are needed to determine the precise mechanism of action of this, otherwise, clinically effective regimen.