a 31-year - old woman presented with a 6-month history of diarrhea , hyperglycemia requiring insulin , weight loss and a 2-month history of icterus and jaundice .
laboratory evaluation revealed elevated liver function tests including alanine aminotransferase ( alt ) of 456 iu / l , aspartate aminotransferase ( ast ) of 233 iu / l , alkaline phosphatase of 791 iu / l , and total bilirubin of 4.4 mg / dl .
abdominal ultrasound showed a pancreatic head mass measuring 5  5  5.5 cm concerning for malignancy . computed tomography ( ct ) of the abdomen confirmed a large pancreatic head mass measuring 5.7  5.7  6.5 cm obstructing both the pancreatic and common bile ducts .
the mass also caused impingement of the superior mesenteric vein ( smv ) and contacted the superior mesenteric artery ( sma ) .
no liver lesions were identified , although several portocaval lymph nodes were noted to be borderline enlarged .
initial attempt to obtain a tissue diagnosis was performed at the time of endoscopic placement of a biliary stent and brushings revealed only reactive ductal epithelium , which was negative for malignancy .
she subsequently underwent an endoscopic ultrasound - guided fine needle aspiration which confirmed a pancreatic neuroendocrine tumor ( pnet ) with neoplastic cells positive for synaptophysin and chromogranin .
serum chromogranin a level was noted to be elevated at 438 mg / ml ( nl < 225 ng / ml ) .
given the absence of evidence for distant disease , the patient was offered surgery and underwent an exploratory laparotomy .
intraoperative visualization of the tumor revealed more extensive vessel involvement than appreciated by ct imaging .
there was encasement of the smv with tumor growth around numerous branches of the sma and extension to the junction of the right renal vein and ivc . based on this appearance ,
an attempt at resection was aborted as a resection with smv reconstruction was not felt to be possible .
her postoperative course was complicated by a pulmonary embolism , which was attributed to recent surgery and underlying malignancy .
standard options including octreotide , sunitinib , and everolimus were considered and offered to the patient .
however , given the patient 's age and disease limited to primary site , it was agreed that the goal of therapy , in this case , should be to achieve tumor shrinkage sufficient to allow a repeat attempt at curative surgical resection .
she ultimately received 8 cycles which she tolerated well while maintaining an excellent performance status .
toxicity was limited to one episode of emesis with each of the first two cycles .
interval imaging done every 2 cycles showed continuous response to therapy with the tumor ultimately measuring 1.9  3.8 cm after cycle 8 ( fig .
although there appeared to be persistent abutment with the smv , there was resolution of impingement of the vein and importantly a clear fat plane was seen around the sma .
based on this significant response to chemotherapy , the patient was offered a second attempt at surgical resection 9 months after her initial surgical exploration .
her tumor was successfully resected without smv resection or reconstruction and final pathology revealed a 2.0  2.5  2.2 cm mass confined to the pancreas with negative margins and 16 lymph nodes resected all negative for metastatic spread .
she did well postoperatively with resolution of hyperglycemia allowing discontinuation of insulin and only occasional diarrhea due to pancreatic insufficiency which improved with pancreatic enzyme replacement .
three months after surgery , she remains free of disease recurrence by imaging and has had normalization of serum chromogranin a level to 206 ng / ml .
pnet is a relatively uncommon tumor that arises in the endocrine cells of the pancreas and is also referred to as pancreatic islet cell tumor .
there is variability in presentation partly dependent on if it is a functional ( hormone - secreting ) or nonfunctional tumor .
functional tumors can produce symptoms related to excess production of hormones such as gastrin , insulin , and glucagon .
the majority of functional tumors are benign but are less prevalent than nonfunctional tumors which are more likely to be malignant .
nonfunctioning tumors typically remain silent until they cause symptoms due to mass effect similar to pancreatic adenocarcinoma .
the overall annual incidence of pnets from 1973 to 2000 was reported to be 0.22 cases per 100,000 with a yearly trend of increased incidence .
a more recent study confirms this trend with an annual incidence of 0.32 per 100,000 cases reported from 2000 to 2004 .
nevertheless , this remains a rare tumor which limits the opportunity to establish clinical trial - based evidence for standard therapy .
the only standard option for advanced disease was a somatostatin analogue . for tumors that are localized with no evidence of distant spread , but are too advanced to surgically resect , there is no evidence to guide optimal management and therefore we are limited to extrapolating results obtained in the advanced metastatic disease setting .
evidence for benefit beyond this was provided by a prospective , randomized placebo - controlled trial by the promid study group which reported an antiproliferative effect of octreotide lar on neuroendocrine midgut tumors .
stable disease was achieved in 66.7% of patients in the octreotide lar group versus stable disease in 37.2% of patients in the placebo group with a median time to tumor progression of 14.3 months in the octreotide lar group and 6 months with the placebo group .
definitive overall survival benefit was limited by crossover of patients in the placebo group to somatostatin analogue treatment at tumor progression .
notably , this particular therapy does not achieve significant tumor regression . in our patient who was free of any symptoms and for whom the goal was to achieve tumor shrinkage ,
more recently , two new drugs , everolimus and sunitinib , have each been approved for treatment of advanced pnets .
everolimus , a mammalian target of rapamycin ( mtor ) inhibitor , was shown to increase progression - free survival in a randomized , placebo - controlled trial .
patients with advanced disease and radiologic evidence of disease progression were found to have an 11.4-month median progression - free survival with everolimus as compared to 5.4 months in the placebo group .
analysis of secondary outcomes showed 5% of patients who received everolimus achieved a partial response by recist criteria .
dose adjustments , either reductions or temporary interruptions , were necessary in 59% of patients and treatment discontinued in 13% due to adverse events .
the most common drug - related adverse events reported were stomatitis , rashes , diarrhea and fatigue .
everolimus was approved by the food and drug administration ( fda ) based on the above survival benefit and although it does not achieve a high rate of tumor shrinkage , it was considered an option in this patient .
sunitinib is a multi - tyrosine kinase inhibitor which has also shown to have activity in patients with pnet . a randomized , double - blinded
, placebo - controlled phase 3 trial was conducted and demonstrated that sunitinib improved progression - free survival when compared to placebo : median 11.4 months versus 5.5 months , respectively . in addition , there was a 9.3% tumor response rate with a median time to tumor response of 3.1 months in patients treated with sunitinib .
the median duration of treatment with sunitinib was only 4.6 months with 22% of patients remaining on the study for over 1 year .
the most common adverse events leading to discontinuation of the drug were fatigue , diarrhea and cardiac failure with dose - limiting toxicity from neutropenia and diarrhea . similar to everolimus , the survival benefit seen in this trial warrants consideration for a patient like ours but again , the < 10% partial response rate tempered our enthusiasm given our goal of down - staging her tumor . although both everolimus and sunitib provide benefit of increased progression - free survival , neither has been shown to achieve significant tumor shrinkage .
numerous phase ii and multi - institutional trials have shown modest benefit with chemotherapeutic agents such as streptozocin , fluorouracil , doxorubicin , gemcitabine , oxaliplatin , temozolomide , thalidomide and capecitabine [ 7 , 8 ] . the specific combination of capecitabine and tomozolomide has been shown in preclinical studies to have in vitro efficacy   and clinical experience was reported in a retrospective study suggesting activity with this well - tolerated combination . in a study done at the moffitt cancer center ,
a cohort of 30 patients with pancreatic endocrine carcinomas were treated with oral capecitabine 750 mg / m twice daily for 14 days and oral temozolomide 200 mg / m daily for 5 days every 28 days with ondansetron given prior to each dose of temozolomide to decrease nausea .
the radiographic response rate in patients with metastatic disease was 70% with a median progression - free survival of 18 months and median duration of radiographic response of 20 months .
the median duration of treatment was 8 cycles , with a range from 3 to 23 cycles .
the majority of side effects were grade 12 thrombocytopenia , hand - foot skin reaction and fatigue .
our patient , with locally advanced disease , was treated with capecitabine and temozolomide for 8 total cycles with the goal of converting her disease to one that would be amenable to a curative surgical resection .
she tolerated therapy well with minimal side effects and 9 months after initial exploratory surgery she ultimately underwent complete resection of a t2n0 tumor with 16 negative lymph nodes and negative margins . considering the relative rarity of pnets , there has undoubtedly been significant progress in the development of treatment options just in the past few years .
everolimus and sunitinib provide options for agents that improve survival primarily through stabilization of disease but lack significant potential to cause tumor shrinkage relevant to locally advanced disease .
chemotherapy with capecitabine and temozolomide appears to be a viable option with potential for a high rate of response that proved to be particularly valuable in our young patient and warrants consideration for clinical trial exploration as neoadjuvant therapy for locally advanced , unresectable pnets .
 pancreatic neuroendocrine tumors ( pnets ) are relatively rare tumors that arise in the endocrine cells of the pancreas . 
 historically , somatostatin analogues have been used in this disease primarily for symptom control and , to a limited extent , disease stability . 
 more recently , sunitinib and everolimus have been approved for advanced stage pnets based on a survival benefit . 
 however , both agents have a < 10% actual response rate and cause nontrivial side effect profiles that limit duration of therapy . in locally advanced disease 
 , there is a paucity of data to support an optimal neoadjuvant approach with the expectation of down - staging to allow for curative resection . 
 we describe in this case a young woman who was successfully down - staged using a chemotherapy regimen of capecitabine and temozolomide with minimal toxicity . 
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