roughly 3040% of patients with pancreatic ductal adenocarcinoma ( pdac ) have locally advanced disease .
their prognosis is not really different from that of patients with metastatic pdac . in about one third of the patients ,
if complete ( r0 ) resection is possible , patients have a similar overall survival ( os ) as those with an initially resectable pdac .
these are the results of a meta - analysis of 111 trials with a total of 4,394 patients and mainly 5-fluorouracil- or gemcitabine - based neoadjuvant chemoradiotherapy .
initially nonresectable patients reached an estimated median os of 20.5 months ( range 962 months ) following resection .
recently , 2 large phase iii trials in patients with metastatic pdac demonstrated encouraging improvements in clinical benefit for 2 combination therapies over single - agent gemcitabine [ 2 , 3 ] . in one trial , the combination of oxaliplatin , 5-fluorouracil , leucovorin and irinotecan ( folfirinox ) significantly improved median os to 11.1 months as compared to 6.8 months for gemcitabine [ hazard ratio ( hr ) 0.57 ; 95% confidence interval ( ci ) 0.450.73 , p < 0.001 ] and median progression - free survival to 6.4 versus 3.3 months ( hr 0.47 ; 95% ci 0.370.59 , p < 0.001 ) , respectively .
the overall response rate with the combination was 31.6 as compared to 9.4% with gemcitabine alone .
the treatment with folfirinox resulted in significantly more adverse events of grade 3 in terms of neutropenia ( 45.7% for folfirinox vs. 21.0% for gemcitabine ) , febrile neutropenia ( 5.4 vs. 1.2% ) , thrombocytopenia ( 9.1 vs. 3.6% ) , diarrhea ( 12.7 vs. 1.8% ) and peripheral neuropathy ( 9.0 vs. 0% ) , while the incidence of alanine aminotransferase elevation was decreased ( 7.3 vs. 20.8% ) .
the combination of nab - paclitaxel plus gemcitabine was studied in the pivotal phase iii trial mpact .
a total of 861 patients with metastatic pdac received first - line chemotherapy either with the combination of nab - paclitaxel at 125 mg / m and gemcitabine at 1,000 mg / m , both administered on days 1 , 8 , 15 , 29 , 36 , and 43 of a 56-day cycle with subsequent cycles on days 1 , 8 , and 15 of a 28-day cycle , or with gemcitabine monotherapy at 1,000 mg / m weekly for 7 out of 8 weeks in the first cycle and in subsequent cycles on days 1 , 8 , and 15 of a 28-day cycle .
median os significantly increased to 8.7 months ( 95% ci 7.899.69 ) as compared to 6.6 months ( 95% ci 6.017.20 ) with gemcitabine alone ( hr 0.72 ; 95% ci 0.6200.825 , p < 0.0001 ) and median progression - free survival was 5.5 versus 3.7 months ( hr 0.69 ; 95% ci 0.580.82 , p < 0.001 ) , respectively .
the combination of nab - paclitaxel plus gemcitabine resulted in an overall response rate of 23 versus 7% with gemcitabine monotherapy ( p < 0.001 ) [ 3 , 4 ] .
the most frequently observed adverse events of grade 3 were neutropenia ( 38% for nab - paclitaxel and gemcitabine vs. 27% for gemcitabine alone ) , leukopenia ( 31 vs. 16% ) , fatigue ( 17 vs. 7% ) and neuropathy ( 17 vs. 1% ) . the results of this trial led to the approval of the combination of nab - paclitaxel and gemcitabine in the european union as the first - line treatment for patients with metastatic pancreatic adenocarcinoma in january 2014 .
thus , both combinations offer a markedly increased efficacy compared to prior standard systemic therapy in the metastatic setting of pdac . based on these encouraging data we treated a patient with an
initially unresectable , locally advanced pdac with a novel neoadjuvant chemotherapy consisting of a sequence of these combination regimens , i.e. nab - paclitaxel plus gemcitabine followed by folfirinox .
in december 2012 , a 46-year - old female patient presented to our center with jaundice .
laboratory findings were typical of cholestasis with an elevated concentration of total serum bilirubin to 8.4 mg / dl .
the level of the tumor marker ca 19 - 9 was increased to 171 u / ml . abdominal ultrasound revealed a dilation of the ductus hepatocholedochus ( dhc ) but no detectable tumor mass .
a stent was placed into the dhc to allow biliary drainage , and as a result total serum bilirubin decreased to a normal value within a few days .
endosonography revealed a hypoechoic lesion in the pancreatic head between dhc and the portal vein in the vicinity of the celiac trunk as well as suspicious locoregional lymph nodes .
there were , however , no tumor cells in the bioptic material gained repeatedly during this session .
integrated fludeoxyglucose ( f ) positron emission tomography ( pet)-computed tomography ( ct ) found a pet - avid tumor in the pancreatic head largely adjacent to the celiac trunk and a pet - avid regional lymph node metastasis ( fig .
an exploratory laparotomy confirmed the diagnosis of pdac by intraoperatively frozen sections and the suspected unresectability which was due to an encasement of the celiac trunk ( > 180 ) by the pancreatic tumor .
thus , the locally advanced pdac could be classified as pt4 nx cm0 g2 . during surgery ,
the patient received a biliodigestive anastomosis using roux - en - y anastomosis and a central venous port system .
three weeks after surgery , intensified neoadjuvant chemotherapy was started with the objective to achieve secondary resectability .
the patient was given 2 cycles of a combination of nab - paclitaxel plus gemcitabine .
nab - paclitaxel was given at a dose of 125 mg / m on days 1 , 8 and 15 , gemcitabine at a dose of 1,000 mg / m on days 1 , 8 and 15 , both repeated on day 29 . chemotherapy was tolerated well .
the follow - up pet - ct showed no more pet - avid lesions ( fig .
oxaliplatin was administered at a dose of 85 mg / m on day 1 , leucovorin at a dose of 400 mg / m on day 1 , and irinotecan at a dose of 180 mg / m on day 1 followed by continuous infusion of 5-fluorouracil over 46 h at a dose of 2,400 mg / m .
side effects were grade 1 neutropenia , grade 2 fatigue , grade 1 diarrhea and grade 1 peripheral neuropathy . the follow - up pet - ct confirmed the complete metabolic remission ; yet , it also showed a persistent tumor abutment of the celiac trunk , formally still unresectable according to nccn guidelines ( fig .
no vital tumor cells were found in the biopsies taken intraoperatively ( frozen sections ) of the tissue surrounding the celiac trunk and the dhc stump .
thus , a pylorus - preserving resection of the pancreatic head , regional lymphadenectomy , pancreaticojejunostomy and antecolic duodenojejunostomy were performed .
thus , the postoperative pathology result was ypt3 ( 2.2 cm ) ypn1 ( 2/33 ; 1 mm ) l0
less than 10% vital tumor cells were found in the resection specimen , corresponding to evans regression score grade iii .
subsequently , the patient was given 2 cycles of adjuvant chemotherapy with gemcitabine from july to september 2013 .
the patient was alive 18 months after the primary diagnosis at the last follow - up visit in april 2014 .
our case shows that secondary r0 resection can be achieved with neoadjuvant chemotherapy utilizing modern combination regimens .
this is relevant as patients with an initially unresectable locally advanced pdac have a similar prognosis to patients with a primarily resectable pancreatic cancer if r0 resection can be achieved .
however , it needs to be stressed that the concept of neoadjuvant therapy in locally advanced unresectable pdac and its actual clinical benefits still have to be proven , since evidence from prospective , randomized trials is still lacking . after a follow - up of 18 months ,
the neoadjuvant chemotherapy we chose was actually a sequence of the 2 most active regimens for metastatic pdac known today .
however , she already showed complete metabolic remission after 2 cycles of nab - paclitaxel plus gemcitabine . in the pivotal trial in metastatic pdac , patients with a biochemical response after nab - paclitaxel plus gemcitabine had a better outcome than patients without a pet - response .
there are also data suggesting that a metabolic pet response may be of predictive value for patients with locally advanced pancreatic carcinoma treated with definitive concurrent chemoradiotherapy .
it is unclear to what extent the sequential treatment with folfirinox improved clinical outcome or whether neoadjuvant chemotherapy with the combination of nab - paclitaxel plus gemcitabine alone would have sufficed
. this will be the objective of the randomized phase ii trial neolap that will start in september 2014 . in this trial , patients with locally advanced , initially unresectable or borderline - resectable pdac will either receive neoadjuvant chemotherapy with 4 cycles of nab - paclitaxel plus gemcitabine or 2 cycles of nab - paclitaxel plus gemcitabine followed by 4 cycles of folfirinox
the primary tumor of our patient showed extensive stromal desmoplasia which is a typical feature of pdac .
the concept of stromal depletion has been identified as a promising therapeutic route in the treatment of pancreatic cancer .
preclinical data show that the treatment with nab - paclitaxel results in depleting desmoplastic stroma and reducing stromal density of pancreatic tumor tissue [ 10 , 11 ] .
the effect of stromal depletion was highest with the combination of nab - paclitaxel and gemcitabine .
there is also clinical evidence from a neoadjuvant trial in 16 patients with resectable pancreatic cancer treated with 2 cycles of nab - paclitaxel plus gemcitabine before surgical resection . of the 12 patients who completed treatment ,
histology showed a change in the architecture of the tumor stroma as indicated by markedly disorganized collagen and a very low density of cancer - associated fibroblasts , which was not observed in the untreated or conventionally treated control groups .
a preclinical , co - clinical study in a mouse model showed that these effects were specific of nab - paclitaxel and not of gemcitabine .
the precise mechanism of stroma depletion by nab - paclitaxel is currently not known and has to be defined in further preclinical and clinical studies . among the multitude of stromal components , the matricellular glycoprotein secreted protein acidic and rich in cysteine ( sparc )
has attracted particular interest . however , despite encouraging data from previous phase i / ii trials , extensive sparc analysis within a phase iii trial ( mpact trial ) failed to demonstrate any prognostic or predictive role of stromal and/or tumor sparc expression in the metastastic setting . in conclusion , chemotherapy with nab - paclitaxel plus gemcitabine followed by folfirinox was an effective and well - tolerated neoadjuvant treatment in a patient with initially irrresectable , locally advanced pdac which resulted in secondary resectability ( r0 resection ) .
not only the clinical benefit of sequencing both combination regimens as neoadjuvant therapy for patients with locally advanced pdac , but also the general concept of neoadjuvant treatment in locally advanced pancreatic cancer needs to be assessed in future prospective clinical trials .
theyare fully responsible for the entire content and all editorial decisions relating to this paper .
 the prognosis of patients with locally advanced pancreatic cancer can be improved if secondary complete ( r0 ) resection is possible . in patients initially staged as unresectable this may be achieved with neoadjuvant treatment which is usually chemoradiotherapy based . 
 we report the case of a 46-year - old patient with an unresectable , locally advanced pancreatic cancer ( pt4 nx cm0 g2 ) who was treated with a sequential neoadjuvant chemotherapy regimen consisting of 2 cycles of nab - paclitaxel plus gemcitabine followed by 4 cycles of folfirinox . 
 neoadjuvant chemotherapy resulted in secondary resectability ( r0 resection ) . 
 after 2 cycles of nab - paclitaxel plus gemcitabine , the patient already had a complete metabolic remission as measured by integrated fludeoxyglucose ( 18f ) positron emission tomography and computerized tomography . 
 after a follow - up of 18 months the patient is alive without progression of disease . 
 we propose to assess the clinical benefit of sequencing the combinations nab - paclitaxel plus gemcitabine and folfirinox as neoadjuvant therapy for patients with locally advanced and initially unresectable pancreatic cancer in a controlled clinical trial . 
Introduction
Case Presentation
Discussion
Disclosure Statement