gastroenteropancreatic neuroendocrine tumors ( gepnets ) are rare malignant neoplasm with an incidence ranging from two to five cases/100,000/yr . because it originates from the enterochromaffin serotonin - producing cell , it has a unique feature of hormone secretion and expression of distinctive differentiation markers [ 1 - 6 ] . some patients remain asymptomatic for several years , or complain of episodic flushing , abdominal pain , nausea , vomiting , and diarrhea . in most cases , due to the vagueness of symptoms , a diagnosis is delayed ( 3 - 10 years on average ) , with an increased risk of developing metastases . the ability of the imaging method to localize primary or metastatic site of gep - net also has some limitations . most gep - nets are highly vascular , thus could easily be detected by a contrast enhanced computed tomography ( ct ) ; however , approximately 6% to 20% are hypovascular and often difficult to be evaluated by a ct scan or other imaging methods . gep - nets originating from jejunum and ileum are also often difficult to identify on an image due to their small size . therefore , non - invasive parameters , indicating gep - pet , are needed for diagnosis , following - ups and prognosis . chromogranin a ( cga ) , a glycoprotein contained in secretion granules of neuroendocrine cells , is the most abundant granin in gep - nets and widely used as a circulating tumor marker , but only few studies have been published on the role of cga in patients with gep - pet , and the range of sensitivity were variously reported [ 8 - 10 ] . we investigated to evaluate whether biochemical response using serial plasma cga is reliable in concordance with the tumor response based on response evaluation criteria in solid tumors ( recist ) criteria in gep - nets irrespective of chemotherapeutic agents . a total of 27 cases in 18 patients , who were pathologically diagnosed in gep - nets , were analysed between march 2011 and september 2013 . for all cases , non - functioning was defined to the absence of clinical syndromes of hormonal hypersecretion , such as hypoglycemia , peptic ulcer , diarrhea , steatorrhea , acromegaly , cushing s syndrome , and gallstone . the following clinicopathological characteristics of all 18 patients were collected : age , sex , primary site , tumor grade in accordance to the 2010 world health organization ( who ) classification , liver metastasis , number of metastatic site , site of metastasis , and information of chemotherapy . systemic chemotherapies for gep - net included octreotide , vip ( vincristine , ifosfamide , cisplatin ) , xelox ( capecitabine , oxaliplatin ) , ep ( etoposide , cisplatin ) , pazopanib , sunitinib , everolimus , and xeliri ( capecitabine , irinotecan ) . biochemical efficacy was estimated according to the criteria proposed by the italian trials in medical oncology ( itmo ) group   for evaluating markers ( biochemical response ) . partial response ( pr ) was defined as  50% decrease in plasma cga compared to the baseline cga ; stable disease ( sd ) was defined as a decrease < 50% or as an increase < 25% ; and progressive disease ( pd ) was defined as an increase  25% . the level of cga was determined from venous blood samples drawn into edta - containing tube after overnight fasting and collected before systemic treatment . the plasma cga level was measured by cga - ria ( chromoa assay , cis bio international , saclay , france ) with a normal range of 27 - 94 ng / ml . chromoa is based on sandwich enzyme - linked immunosorbent assay , using two monoclonal antibodies ( the same antibodies as cga - riact ) directed against the central domain of the molecule ( 145 - 245 ) , which is less sensitive to proteolysis . the tumor size was measured by using a ct or magnetic resonance imaging by recist criteria ver . 1.1 . group comparisons were performed using a nonparametric test of mann - whitney or kruskal - wallis , followed by a dunn multiple comparison test , as appropriate . comparisons of paired values were performed using a nonparametric test of wilcoxon . the chi - square test and the fisher exact test ( for value less than 5 ) were employed to compare the sensitivity and rate of concordance in different groups . in all statistical tests , progression - free survival ( pfs ) was measured as the time from the date of chemotherapy to the date of first documented disease progression or death . the pfs were estimated using the kaplan - meier method with log - rank analysis . a total of 27 cases in 18 patients , who were pathologically diagnosed in gep - nets , were analysed between march 2011 and september 2013 . for all cases , non - functioning was defined to the absence of clinical syndromes of hormonal hypersecretion , such as hypoglycemia , peptic ulcer , diarrhea , steatorrhea , acromegaly , cushing s syndrome , and gallstone . the following clinicopathological characteristics of all 18 patients were collected : age , sex , primary site , tumor grade in accordance to the 2010 world health organization ( who ) classification , liver metastasis , number of metastatic site , site of metastasis , and information of chemotherapy . systemic chemotherapies for gep - net included octreotide , vip ( vincristine , ifosfamide , cisplatin ) , xelox ( capecitabine , oxaliplatin ) , ep ( etoposide , cisplatin ) , pazopanib , sunitinib , everolimus , and xeliri ( capecitabine , irinotecan ) . biochemical efficacy was estimated according to the criteria proposed by the italian trials in medical oncology ( itmo ) group   for evaluating markers ( biochemical response ) . partial response ( pr ) was defined as  50% decrease in plasma cga compared to the baseline cga ; stable disease ( sd ) was defined as a decrease < 50% or as an increase < 25% ; and progressive disease ( pd ) was defined as an increase  25% . the level of cga was determined from venous blood samples drawn into edta - containing tube after overnight fasting and collected before systemic treatment . the plasma cga level was measured by cga - ria ( chromoa assay , cis bio international , saclay , france ) with a normal range of 27 - 94 ng / ml . chromoa is based on sandwich enzyme - linked immunosorbent assay , using two monoclonal antibodies ( the same antibodies as cga - riact ) directed against the central domain of the molecule ( 145 - 245 ) , which is less sensitive to proteolysis . the tumor size was measured by using a ct or magnetic resonance imaging by recist criteria ver . group comparisons were performed using a nonparametric test of mann - whitney or kruskal - wallis , followed by a dunn multiple comparison test , as appropriate . comparisons of paired values were performed using a nonparametric test of wilcoxon . the chi - square test and the fisher exact test ( for value less than 5 ) were employed to compare the sensitivity and rate of concordance in different groups . in all statistical tests , progression - free survival ( pfs ) was measured as the time from the date of chemotherapy to the date of first documented disease progression or death . the pfs were estimated using the kaplan - meier method with log - rank analysis . the rectum was the second most common site of gep - net ( 22.2% ) in this study . according to who classification , ten of the 27 cases ( 37% ) were grade 3 neuroendocrine carcinoma . grades 1 and 2 nets were nine ( 33.3% ) and eight ( 29.6% ) , respectively . measurable lesions were found on ct images in 18 out of the 27 cases . among the 27 cases included in this study , no difference in the basal cga level was observed in terms of gender , primary tumor site , tumor grade ( who classification ) , liver metastasis , number of metastatic site , and line of chemotherapy with serial cga monitoring . the plasma cga level ranged from 33.18 to 895 ng / ml ( table 1 ) . the overall response rate ( rr ) by recist criteria was six out of the 27 cases ( 22.2% ) and eight out of the 27 cases ( 29.6% ) for biochemical rr . the concordance of response between recist criteria and biochemical criteria were 74% ( table 3 ) . compared with the baseline values , a decrease of  50% in the cga level were observed in three out of six cases ( 50% ) with pr by recist criteria ( figs . 1a , 2 ) . in only grades 1 and 2 gep - nets cases ( n=17 ) , the concordance of disease control between recist criteria and biochemical criteria were 94.1% ( fig . there was a significant difference for pfs between responders and non - responders ( 35.73 months vs. 5.93 months , p=0.05 ) based on the biochemical criteria ( fig . 3 ) . a subgroup analysis of pfs between responders and non - responders , in accordance to recist response , tumor grade , and primary site , were not statistically significant , but showed longer pfs in the biochemical responder group ( fig . the rectum was the second most common site of gep - net ( 22.2% ) in this study . according to who classification , ten of the 27 cases ( 37% ) were grade 3 neuroendocrine carcinoma . grades 1 and 2 nets were nine ( 33.3% ) and eight ( 29.6% ) , respectively . among the 27 cases included in this study , no difference in the basal cga level was observed in terms of gender , primary tumor site , tumor grade ( who classification ) , liver metastasis , number of metastatic site , and line of chemotherapy with serial cga monitoring . the plasma cga level ranged from 33.18 to 895 ng / ml ( table 1 ) . the overall response rate ( rr ) by recist criteria was six out of the 27 cases ( 22.2% ) and eight out of the 27 cases ( 29.6% ) for biochemical rr . the concordance of response between recist criteria and biochemical criteria were 74% ( table 3 ) . compared with the baseline values , a decrease of  50% in the cga level were observed in three out of six cases ( 50% ) with pr by recist criteria ( figs . 1a , 2 ) . in only grades 1 and 2 gep - nets cases ( n=17 ) , the concordance of disease control between recist criteria and biochemical criteria were 94.1% ( fig . there was a significant difference for pfs between responders and non - responders ( 35.73 months vs. 5.93 months , p=0.05 ) based on the biochemical criteria ( fig . 3 ) . a subgroup analysis of pfs between responders and non - responders , in accordance to recist response , tumor grade , and primary site , were not statistically significant , but showed longer pfs in the biochemical responder group ( fig . cga is the most abundant granin in gep - nets and represents the best general marker in the tissue and blood . cga expression generally correlates with the number of dense core granules in the neuroendocrine cells . thus , cga monitoring may be helpful in assessing the response to the different therapeutic options . in some studies , however , it is still controversial whether serial cga changes reflect tumor response for treatment . this study showed that the change of the cga level was correlated with tumor response in nonfunctioning gepnets . additionally , biochemical response based on serial cga may be a predictive marker for pfs in gep - nets . changes in circulating cga have been reported to represent tumor burden and treatment response . to our knowledge , there were no definite measuring criteria of plasma cga for tumor response and conflicting result of sensitivity and specificity in accordance to treatment response were reported in the literature . previous studies [ 2 - 10,18 ] showed acceptable sensitivity ( 54%-78% ) and specificity ( 60%-86% ) for regression and sd ; jensen et al .   also reported that plasma cga concentration is important to disclose tumor progression with specificity and sensitivity , 86% and 86% , respectively . in our study , the concordance of response between recist criteria and biochemical criteria was 74% . compared with the baseline values , a decrease of  25% in the cga level was observed in four out of six patients ( 66.7% ) with pr based on recist criteria and an increased cga levels was shown in all 4 patients with pd ( 100% ) . among 11 patients available for serial cga levels , all five patients with sd or partial remission had a more than 20% decrease in the cga levels compared to the baseline value . all six patients with pd showed a less than 20% decrease or increase in the cga levels . several other studies also showed the possibility of cga as a biochemical marker of treatment response ( table 4 ) . high - baseline cga value has been considered to be an independent poor prognostic marker for gep - nets in previous studies [ 21 - 25 ] . however , whether changes of the cga levels compared to the baseline values could predict the prognosis has not been established . in this study , there was a significant difference for pfs between the responders and non - responders for biochemical criteria ( p=0.05 ) . it suggested that a decrease in the cga levels from the baseline levels may be an important predictive marker for survival in gep - nets . this study was a retrospective analysis with small sample size , and heterogeneous patient population . a recognized international standard for cga assay is not available and variations in assay types may influence results . nevertheless , this analysis identified the usefulness of serial cga monitoring as a biomarker that predicts treatment response and survival . this study revealed that the changes of the plasma cga levels were associated with tumour response . additionally , biochemical response based on serial cga may be a predictive marker for pfs in gep - nets .
purposechromogranin a ( cga ) has been considered to be valuable not only in the diagnosis but also in monitoring the disease response to treatment . however , only a few studies have been published on this issue . we purposed to evaluate whether biochemical response using plasma cga level is reliable in concordance with the clinical response of grade 1 - 3 nonfunctiong gastroenteropancreatic neuroendocrine tumors ( gep - nets).materials and methodsbetween march 2011 and september 2013 , a total of 27 cases in 18 patients were analysed , clinically and radiologically while serial cga tests were also conducted during treatment . 
 tumor responses were defined by both response evaluation criteria in solid tumors ( recist ) criteria ver . 
 1.1 and biochemical criteria based on the cga level.resultsamong the 27 cases analysed , no difference in the basal cga level was observed with regard to gender , primary tumor site , tumor grade ( world health organization classification ) , liver metastasis , number of metastatic site , and line of chemotherapy . 
 the overall response rate ( rr ) by recist criteria ver . 
 1.1 was six out of the 27 cases ( 22.2% ) and eight out of the 27 cases ( 29.6% ) for biochemical rr . 
 the overall concordance rates of the response based on recist and biochemical criteria were 74% . in grades 1 and 2 gep - nets ( n=17 ) , 
 the concordance rate of the disease control was 94.1% . 
 there was a significant difference for progression - free survival ( pfs ) between responders and non - responder in accordance to biochemical criteria ( 35.73 months vs. 5.93 months , p=0.05).conclusionthis study revealed that changes of the plasma cga levels were associated with tumour response . 
 additionally , biochemical response based on serial cga may be a predictive marker for pfs in gep - nets .