The drug gemcitabine is generally well tolerated, but its efficacy for pancreatic cancer (ductal adenocarcinoma of the pancreas) when used as a solitary chemotherapy is now understood to not be as great as that of use in combination with Abraxane, or as that of the four-drug chemotherapy combination regimen – FOLFIRINOX. However these combination chemotherapy regimens for pancreatic cancer tend to carry more frequent and severe adverse effects.
Gemcitabine is a hydrophilic nucleoside analog, and consequently must be carried by cell membrane transporters to penetrate the hydrophobic cell wall in order to initiate its cytotoxic anti-pancreatic-tumor activity. The main membrane carrier for gemcitabine is considered to be hENT1 (human equilibrative nucleoside transporter 1). Past retrospective studies with gemcitabine used as adjuvant therapy for pancreatic cancer, though somewhat conflicting, generally appear to suggest that increased levels of hENT1 may be associated with a greater than expected survival advantage.
The authors, from the Università Cattolica del Sacro Cuore in Rome, Italy, conducted a retrospective analysis to better understand the relationship between hENT1 expression as an indicator of gemcitabine chemotherapy outcomes in pancreatic cancer. And more specifically, to determine the survival characteristics in pancreatic cancer of the less toxic monotherapy as compared to the generally more efficacious but more toxic combination regimen of FOLFIRINOX, especially in terms of those pancreatic cancer patients demonstrating hyperexpression of hENT1. The results of this study were published in the October 2016 issue of Clinical & Translational Oncology (the official journal of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico).
The researchers reviewed the records of 149 patients with locally advanced and metastatic pancreatic cancer who had been treated in their institution from 2009 until 2013. They found that 70 of patients’ records were evaluable (36 FOLFIRINOX and 34 gemcitabine monotherapy). The authors also found that 31 patients had stored pancreatic cancer tumor tissue with enough RNA to evaluate hENT1 levels. The median overall survival was significantly longer in duration in the FOLFIRINOX as compared to the gemcitabine group (11 months vs. 8 months). Also, the FOLFIRINOX arm showed a statistically greater incidence of Grade 3 and 4 adverse effects over gemcitabine, especially neutropenia, diarrhea, and sensory neuropathy. These outcomes were seen as consistent with what has come to be expected in the treatment of pancreatic cancer.
The authors now did something very clever. They assayed hENT1 levels from pancreatic tissue in three healthy controls. In this manner, they established a median hENT1 level which served as a border for the purposes of the remainder of the study. Results found to lie below this median level were assumed to represent low hENT1 expression, and those above this cut-off were assumed to be hyperexpression of hENT1.
Of the 31 patients who had pancreatic tissue for analysis, 12 were classified as having low hENT1 levels, and 19 patients were found to carry hENT1 hyperexpression. Seven of the hENT1 hyperexpressors had received FOLFIRINOX; twelve received gemcitabine. Seven of the hENT1 hypoexpressors had received FOLFIRINOX, five received gemcitabine.
The key finding of this study is that within the hENT1 hyperexpressors in pancreatic cancer there was no statistical difference in overall survival and in progression free survival between the FOLFIRINOX and the gemcitabine monotherapy groups. (OS FOLFIRINOX 8.5 months; gemcitabine 7 months). Further, the overall survival of the 12 hENT1 hyperexpressors treated with gemcitabine was significantly greater than the 5 hypoexpressors treated with gemcitabine (8 months vs. 2 months). The FOLFIRINOX expression subgroups with pancreatic cancer did not show any statistical difference in survival.
In the discussion section of the paper, the authors note the small sample size as a possible limitation of the study. The implications of these results certainly appear to be worth future replication attempts with a much larger study population. The identification of those pancreatic cancer patients who might do as well with less toxic gemcitabine monotherapy over combination chemotherapy could confer a considerable quality of life benefit.
Dale O’Brien, MD