the incidence of esophageal cancer has increased in recent years , reflecting a shift in histologic type and primary tumor location in the west .
although adenocarcinoma of the esophagus is more prevalent in western countries , squamous cell carcinoma is still the most prominent histologic type worldwide .
esophageal cancer is a highly aggressive disease with a 3-year survival rate of less than 1% .
approximately 50% of patients have distant metastasis at the time of diagnosis , and of the remaining patients who initially present with only locoregional disease , 25% develop distant metastases .
compared to other solid tumors , randomized phase iii trials to test the efficacy of cytotoxic chemotherapy are lacking for metastatic esophageal squamous cell carcinoma ( mescc ) .
one randomized phase ii study published in europe more than 20 years ago showed that a combination of cisplatin / fluorouracil ( 5-fu ) ( fp ) was superior to cisplatin alone ( response rate , 35% vs. 19% , respectively ) , although no clear improvement in overall survival ( os ) was observed ( 33 weeks vs. 28 weeks , respectively ) .
hematological and non - hematological toxicities were more prominent in the combination treatment arm , with aplasia and septicemia being the most frequent toxicities observed .
treatment - related deaths were observed in seven patients ( 16% ) in the combination treatment arm , whereas no treatment - related deaths were observed in the cisplatin alone treatment arm .
in contrast , another phase ii study investigating capecitabine / cisplatin combination therapy in a different ethnic population showed promising anti - tumor activity , with a 57.8% response rate and more tolerable toxicity levels .
the combination of cisplatin and 5-fu is the most commonly used regimen as first - line chemotherapy for mescc .
however , the differences in treatment responses and toxicity levels in these two different clinical trial study populations highlight the difficulty in determining the most effective treatment regimens for mescc patients .
these studies further illustrate the importance of identifying patients who would benefit from cytotoxic chemotherapy .
here , we developed and validated a prognostic nomogram to predict survival that will aid physicians and patients in making an appropriate clinical decision regarding treatment .
this study was approved by the institutional review board ( irb ) of the samsung medical center , seoul , south korea and is registered on clinicaltrials.gov ( nct#nct 01472419 ) .
the informed consent form was waived by the irb . between january 2000 to december 2010 , 239 patients were diagnosed with recurrent mescc and received either fp or capecitabine / cisplatin ( xp ) as first - line chemotherapy .
the following clinicopathologic variables and treatment outcomes were collected : patient demographics , laboratory data at the time of first - line palliative chemotherapy , surgical record , pathologic report , tnm stage , treatment record , and vital status .
fp and xp regimens used to treat the patients are described below . in the fp group , 5-fu and
5-fu ( 1,000 mg / m ) was infused over 24 hours during the four days .
cisplatin was given in one dose of 60 mg / m at the beginning of each cycle . in the xp group ,
capecitabine ( 1,250 mg / m bid ) was administered for 14 days and cisplatin was given in one dose of 60 mg / m at the beginning of each cycle .
the clinical tumor response was assessed according to world health organization ( who ) criteria or response evaluation criteria in solid tumors criteria ( recist 1.0 ) . as an external validation data set
, 61 patients with mescc who received palliative fluoropyrimidine / platinum chemotherapy ( xp or fp ) at northern france cancer center were included .
the primary endpoints of the study were os and progression - free survival ( pfs ) .
os was measured from the date of first chemotherapy to the date of death or the last follow - up visit , and pfs was calculated from the date of first chemotherapy to the date of progression .
a prognostic model was established by identifying all variables that significantly influenced os or pfs at a p - value less than or equal to 0.05 in univariate analysis .
factors included in the multivariate analyses were the following : age , sex , performance status , previous esophagectomy , weight loss ( 10% of weight lost for 3 months ) at the time of chemotherapy , stent or percutaneous endoscopic gastrostomy , tracheoesophageal fistula , primary tumor location , histologic tumor grade , and metastatic site ( lung , liver , bone , and adrenal gland ) .
in addition , laboratory findings at the time of chemotherapy were included as categorical variables based on the normal ranges and consisted of the following : hemoglobin ( > 11.2 g / dl vs. 11.2 g / dl ) , white blood cell count ( > 8,630/l vs. 8,630/l ) , platelet count ( > 13810/l vs. 13810/l ) , serum albumin ( > 3.5 g / dl vs. 3.5 g / dl ) , total bilirubin ( > 1.5 mg / dl vs. 1.5 mg / dl ) , aspartate aminotransferase ( > 40 u / l vs. 40
u / l ) , and serum creatinine ( > 1.1 mg / dl vs. 1.1 mg / dl ) .
a nomogram was developed as a prognostic scoring system incorporating significant clinical and laboratory variables based on a multivariate cox proportional hazards regression model .
for example , the predicted 12-month os hazard rate was calculated as follows : 12 months os hazard rate=0.06501exp ( 0.6755ecog 0 - 1 [ if the ecog grade was 0 - 1 , the score could be 1 , if not , the score is 0])+1.0682ecog 2 ( if the ecog grade1 was 2 , the score could be 1 , if not , the score is 0)+0.3784weight loss ( absence of weight loss=0 , presence of weight loss=1)-0.6562albumin ( if serum albumin > 3.5 g / dl , the score is 1 , if serum albumin 3.5 g / dl , the score is 0)-0.2848previous esophagectomy ( absence=0 , presence=1 ) .
the nomogram was then constructed using coefficients from the cox proportional hazard model for convenience . on the basis of the nomogram
, patients were categorized into three groups according to their risk score percentile : favorable ( 0 - 50 percentile ) , intermediate ( 50 - 75 percentile ) , and poor ( 75 - 100 percentile ) risk score .
discrimination was examined using the area under the receiver operating characteristic ( roc ) curve ( auc ) . for internal validation
, random sampling was repeated with replacement using the bootstrapping method over 1,000 times , and a new bias - corrected 95% confidence interval ( ci ) for auc was calculated using r 2.13.2 ( r foundation for statistical computing , vienna , austria ; isbn 3 - 900051 - 07 - 0 ; http://www.r-project.org ) .
this study was approved by the institutional review board ( irb ) of the samsung medical center , seoul , south korea and is registered on clinicaltrials.gov ( nct#nct 01472419 ) .
the informed consent form was waived by the irb . between january 2000 to december 2010 , 239 patients were diagnosed with recurrent mescc and received either fp or capecitabine / cisplatin ( xp ) as first - line chemotherapy .
the following clinicopathologic variables and treatment outcomes were collected : patient demographics , laboratory data at the time of first - line palliative chemotherapy , surgical record , pathologic report , tnm stage , treatment record , and vital status .
fp and xp regimens used to treat the patients are described below . in the fp group , 5-fu and
5-fu ( 1,000 mg / m ) was infused over 24 hours during the four days .
cisplatin was given in one dose of 60 mg / m at the beginning of each cycle . in the xp group ,
capecitabine ( 1,250 mg / m bid ) was administered for 14 days and cisplatin was given in one dose of 60 mg / m at the beginning of each cycle .
the clinical tumor response was assessed according to world health organization ( who ) criteria or response evaluation criteria in solid tumors criteria ( recist 1.0 ) .
as an external validation data set , 61 patients with mescc who received palliative fluoropyrimidine / platinum chemotherapy ( xp or fp ) at northern france cancer center were included .
the primary endpoints of the study were os and progression - free survival ( pfs ) .
os was measured from the date of first chemotherapy to the date of death or the last follow - up visit , and pfs was calculated from the date of first chemotherapy to the date of progression . os and pfs were estimated using the kaplan - meier product - limit method .
a prognostic model was established by identifying all variables that significantly influenced os or pfs at a p - value less than or equal to 0.05 in univariate analysis .
factors included in the multivariate analyses were the following : age , sex , performance status , previous esophagectomy , weight loss ( 10% of weight lost for 3 months ) at the time of chemotherapy , stent or percutaneous endoscopic gastrostomy , tracheoesophageal fistula , primary tumor location , histologic tumor grade , and metastatic site ( lung , liver , bone , and adrenal gland ) .
in addition , laboratory findings at the time of chemotherapy were included as categorical variables based on the normal ranges and consisted of the following : hemoglobin ( > 11.2 g / dl vs. 11.2 g / dl ) , white blood cell count ( > 8,630/l vs. 8,630/l ) , platelet count ( > 13810/l vs. 13810/l ) , serum albumin ( > 3.5 g / dl vs. 3.5 g / dl ) , total bilirubin ( > 1.5 mg / dl vs. 1.5 mg / dl ) , aspartate aminotransferase ( > 40
u / l ) , and serum creatinine ( > 1.1 mg / dl vs. 1.1 mg / dl ) .
a nomogram was developed as a prognostic scoring system incorporating significant clinical and laboratory variables based on a multivariate cox proportional hazards regression model .
for example , the predicted 12-month os hazard rate was calculated as follows : 12 months os hazard rate=0.06501exp ( 0.6755ecog 0 - 1 [ if the ecog grade was 0 - 1 , the score could be 1 , if not , the score is 0])+1.0682ecog 2 ( if the ecog grade1 was 2 , the score could be 1 , if not , the score is 0)+0.3784weight loss ( absence of weight loss=0 , presence of weight loss=1)-0.6562albumin ( if serum albumin > 3.5 g / dl , the score is 1 , if serum albumin 3.5 g / dl , the score is 0)-0.2848previous esophagectomy ( absence=0 , presence=1 ) .
the nomogram was then constructed using coefficients from the cox proportional hazard model for convenience . on the basis of the nomogram
, patients were categorized into three groups according to their risk score percentile : favorable ( 0 - 50 percentile ) , intermediate ( 50 - 75 percentile ) , and poor ( 75 - 100 percentile ) risk score .
discrimination was examined using the area under the receiver operating characteristic ( roc ) curve ( auc ) . for internal validation
, random sampling was repeated with replacement using the bootstrapping method over 1,000 times , and a new bias - corrected 95% confidence interval ( ci ) for auc was calculated using r 2.13.2 ( r foundation for statistical computing , vienna , austria ; isbn 3 - 900051 - 07 - 0 ; http://www.r-project.org ) .
between january 2000 to december 2010 , 239 mescc patients were treated with either fp or xp chemotherapy .
the median age of the patients was 62 with a range of 40 to 79 .
two hundred and twenty - five patients ( 94.1% ) had an eastern cooperative oncology group ( ecog ) performance score of 0 to 1 at the time of chemotherapy .
ninety - three patients developed recurrence even after curative resection ( n=93 ) , and 11 patients showed recurrence after definitive concurrent chemo and radiotherapy . the other 135 patients ( 56.5% ) were diagnosed with metastatic disease at initial presentation .
the most common metastatic site was the lung ( n=97 ) followed by the liver ( n=36 ) .
sixty percent ( n=143 ) of patients received fp and 40% received xp treatment as first - line chemotherapy .
no significant differences in baseline characteristics were observed between the xp and fp groups , except for the proportion of patients who received esophagectomy ( data not shown ) .
the median age of this group of patients was 56 , with a range of 42 to 77 , and all patients received palliative fluoropyrimidine / platinum chemotherapy .
again , no significant differences in baseline characteristics were observed between the fp and xp groups .
the patients in the validation set had fewer previous esophagectomies , more lung and liver metastases , and poorer performance status scores as a group than the patients in the training set .
univariate analyses revealed that poor ecog score , weight loss ( loss of at least 10% of weight for 3 months ) , absence of previous esophagectomy , low hemoglobin level ( 11.2 g / dl ) , and low albumin level ( 3.5 g / dl ) were significantly associated with low os .
moreover , poor ecog score , weight loss , absence of previous esophagectomy , low albumin level , leukocytosis ( > 8,630/l ) , elevated alanine aminotransferase level , and the presence of liver metastasis predicted short pfs in univariate analysis ( table 2 ) .
multivariate analysis showed that poor performance status ( ecog2 ) ( p=0.01 ) , low albumin level ( p<0.01 ) , previous esophagectomy ( p<0.01 ) , and weight loss ( p=0.04 ) at the time of chemotherapy retained statistical significance to predict poor survival ( table 3 ) .
previous esophagectomy ( p=0.03 ) and low albumin level ( p<0.01 ) were also significant for predicting pfs in multivariate analysis . to build a nomogram to predict survival following frontline palliative chemotherapy in mescc
, a scoring system was constructed that incorporates significant variables such as performance status scores , weight loss , low albumin levels , and previous esophagectomy ( fig .
, patients were categorized into ecog 0 , 1 , or 2 and scored at 0 , 63 , or 100 points , respectively , based on the cox regression model . for other variables ,
the scoring system was as follows : weight loss ( + ) vs. ( - ) ( 35 points vs. 0 points ) , low albumin vs. normal albumin ( 61 points vs. 0 points ) , and esophagectomy ( + ) vs. ( - ) ( 27 points vs. 0 points ) .
patients were then categorized into three groups by risk scores based on the nomogram : favorable ( score 0 - 90 , n=119 ) , intermediate risk ( score 91 - 135 , n=58 ) , and poor ( score > 135 , n=61 ) risk score ( table 4 ) .
the nomogram could discriminate between risk groups very well with the following median os for each risk group : favorable risk group , 13.8 months ( 95% confidence interval [ ci ] , 10.82 to 18.58 months ) ; intermediate risk group , 11.2 months ( 95% ci , 8.7 to 11.89 months ) ; and poor risk group ( 7.0 months ; 95% ci , 3.56 to 10.04 months ; p<0.001 ) ( fig .
similar to the os findings , the nomogram significantly identified the pfs of the three groups as follows : favorable risk group , 5.9 months ( 95% ci , 4.6 to 7.2 months ) ; intermediate risk group , 4.3 months ( 95% ci , 3.3 to 5.3 months ) ; and poor risk group , 3.0 months ( 95% ci , 2.3 to 3.8 months ) ( p<0.001 ) ( fig .
the calibration curve showed the robustness of the nomogram to predict os probability at 12 months ( fig .
the nomogram was internally validated by repeated random sampling with replacement by bootstrapping over 1,000 times , yielding a bias - corrected 95% ci for auc of 0.59 to 0.74 , in accord with the 95% ci for auc ( 0.58 - 0.74 ) .
the nomogram was also assessed on an external validation data set and discriminated the three risk groups with survival curves significantly similar to those obtained for the training data set ( fig .
the median os according to risk groups were : favorable risk group , 15.5 months ; intermediate risk group , 7.8 months ; and poor risk group , 5.1 months ( p<0.001 ) ( fig .
between january 2000 to december 2010 , 239 mescc patients were treated with either fp or xp chemotherapy .
the median age of the patients was 62 with a range of 40 to 79 .
two hundred and twenty - five patients ( 94.1% ) had an eastern cooperative oncology group ( ecog ) performance score of 0 to 1 at the time of chemotherapy .
ninety - three patients developed recurrence even after curative resection ( n=93 ) , and 11 patients showed recurrence after definitive concurrent chemo and radiotherapy . the other 135 patients ( 56.5% ) were diagnosed with metastatic disease at initial presentation .
the most common metastatic site was the lung ( n=97 ) followed by the liver ( n=36 ) .
sixty percent ( n=143 ) of patients received fp and 40% received xp treatment as first - line chemotherapy .
no significant differences in baseline characteristics were observed between the xp and fp groups , except for the proportion of patients who received esophagectomy ( data not shown ) .
the median age of this group of patients was 56 , with a range of 42 to 77 , and all patients received palliative fluoropyrimidine / platinum chemotherapy .
again , no significant differences in baseline characteristics were observed between the fp and xp groups .
the patients in the validation set had fewer previous esophagectomies , more lung and liver metastases , and poorer performance status scores as a group than the patients in the training set .
univariate analyses revealed that poor ecog score , weight loss ( loss of at least 10% of weight for 3 months ) , absence of previous esophagectomy , low hemoglobin level ( 11.2 g / dl ) , and low albumin level ( 3.5 g / dl ) were significantly associated with low os .
moreover , poor ecog score , weight loss , absence of previous esophagectomy , low albumin level , leukocytosis ( > 8,630/l ) , elevated alanine aminotransferase level , and the presence of liver metastasis predicted short pfs in univariate analysis ( table 2 ) . multivariate analysis showed that poor performance status ( ecog2 ) ( p=0.01 ) , low albumin level ( p<0.01 ) , previous esophagectomy ( p<0.01 ) , and weight loss ( p=0.04 ) at the time of chemotherapy retained statistical significance to predict poor survival ( table 3 ) .
previous esophagectomy ( p=0.03 ) and low albumin level ( p<0.01 ) were also significant for predicting pfs in multivariate analysis . to build a nomogram to predict survival following frontline palliative chemotherapy in mescc
, a scoring system was constructed that incorporates significant variables such as performance status scores , weight loss , low albumin levels , and previous esophagectomy ( fig .
, patients were categorized into ecog 0 , 1 , or 2 and scored at 0 , 63 , or 100 points , respectively , based on the cox regression model . for other variables ,
the scoring system was as follows : weight loss ( + ) vs. ( - ) ( 35 points vs. 0 points ) , low albumin vs. normal albumin ( 61 points vs. 0 points ) , and esophagectomy ( + ) vs. ( - ) ( 27 points vs. 0 points ) .
patients were then categorized into three groups by risk scores based on the nomogram : favorable ( score 0 - 90 , n=119 ) , intermediate risk ( score 91 - 135 , n=58 ) , and poor ( score > 135 , n=61 ) risk score ( table 4 ) .
the nomogram could discriminate between risk groups very well with the following median os for each risk group : favorable risk group , 13.8 months ( 95% confidence interval [ ci ] , 10.82 to 18.58 months ) ; intermediate risk group , 11.2 months ( 95% ci , 8.7 to 11.89 months ) ; and poor risk group ( 7.0 months ; 95% ci , 3.56 to 10.04 months ; p<0.001 ) ( fig .
2 ) . the nomogram was applied in the same patient cohort to predict pfs . similar to the os findings , the nomogram significantly identified the pfs of the three groups as follows : favorable risk group , 5.9 months ( 95% ci , 4.6 to 7.2 months ) ; intermediate risk group , 4.3 months ( 95% ci , 3.3 to 5.3 months ) ; and poor risk group , 3.0 months ( 95% ci , 2.3 to 3.8 months ) ( p<0.001 ) ( fig .
the calibration curve showed the robustness of the nomogram to predict os probability at 12 months ( fig .
the nomogram was internally validated by repeated random sampling with replacement by bootstrapping over 1,000 times , yielding a bias - corrected 95% ci for auc of 0.59 to 0.74 , in accord with the 95% ci for auc ( 0.58 - 0.74 ) .
the nomogram was also assessed on an external validation data set and discriminated the three risk groups with survival curves significantly similar to those obtained for the training data set ( fig .
the median os according to risk groups were : favorable risk group , 15.5 months ; intermediate risk group , 7.8 months ; and poor risk group , 5.1 months ( p<0.001 ) ( fig .
this is largely because of the absence of largescale phase iii randomized clinical trials , since mescc is included as part of esophageal adenocarcinoma / gastric cancer in most trials . despite the lack of clear evidence that palliative chemotherapy confers a survival benefit in mescc , many physicians are firmly convinced that chemotherapy has a favorable impact on outcome because some drugs ( or combination of cytotoxic agents ) have shown antitumor activity in phase ii trials [ 6,8 - 11 ] .
these discrepancies between what is known and what is done mean that practice patterns differ greatly between continents , countries , and institutions .
moreover , no guidelines exist to select patients who might benefit the most from chemotherapy . only a few studies to date have focused on prognostication of mescc with palliative chemotherapy .
one study analyzed 351 patients either with adenocarcinoma or with squamous cell carcinoma and found that performance status and the extent of disease predict treatment outcome .
the major limitation of this study was the heterogeneous patient population and the variety of chemotherapeutic regimens used .
another large - scaled prognostication paper included 1,080 patients from three randomized trials although only 50 patients had mescc .
the largest study was reported by a french group who analyzed 284 patients , of whom 80% had mescc .
this study identified dysphagia and the occurrence of a second primary cancer as independent predictors of poor outcome in a first set of 171 patients and validated these findings in a second set of 113 patients .
however , when survival was adjusted with these prognostic factors , they found that chemotherapy did not substantially alter the natural course of mescc . in our study , we found that poor performance status ( ecog2 ) , low albumin level ( 3.5g / dl ) , absence of previous esophagectomy , and weight loss ( at least 10% for 3 months ) significantly predicted poor survival and short pfs following first - line fluoropyrimidine / cisplatin chemotherapy .
it is worth noting that all of these factors , although independent prognosticators , are more or less related to nutritional matters in esophageal cancer .
hence , the actual benefit from chemotherapy in mescc patients with poor nutritional status as indicated by low albumin , poor performance or weight loss needs to be taken into consideration during decision making .
the greatest advantage of our nomogram is that it is based on clinical parameters that are prospectively collected before chemotherapy .
the robustness of the model was demonstrated using internal validation via the bootstrapping method as well as external validation on a series of french patients with mescc who received an fp regimen .
our study is also the largest study analyzing the prognostic factors of outcome in mescc treated with a fluoropyrimidine / cisplatin regimen , the most commonly used and most efficient regimen according to a review of 96 different trials performed by grunberger et al . .
, the nomogram developed here predicts survival in mescc and should aid physicians and patients in decision - making regarding the use of fp chemotherapy .
this nomogram may also be useful in stratifying patients in future clinical trials , similar to what is currently being done in an ongoing randomized phase ii trial for mescc ( clinicaltrials.gov nct # nct00816634 ) .
the nomogram including the variables , ecog performance , albumin , weight loss and previous esophagectomy predicts survival in mescc patients and could serve as a guide for the use of fp / xp chemotherapy in mescc patients .
 purposethe degree of benefit from palliative chemotherapy differs widely among patients with metastatic esophageal squamous cell carcinoma ( mescc ) . 
 the purpose of this study was to develop and validate a prognostic nomogram to predict survival and aid physicians and patients in the decision - making process regarding treatment options.materials and methodsclinicopathologic variables and treatment outcomes of 239 patients who were diagnosed with mescc and received either fluorouracil / cisplatin ( fp ) or capecitabine / cisplatin ( xp ) as first - line chemotherapy were reviewed . 
 a nomogram was developed as a prognostic scoring system incorporating significant clinical and laboratory variables based on a multivariate cox proportional hazards regression model . 
 an independent series of 61 mescc patients treated with fp served as an independent data set for nomogram validation.resultsno difference in response rate was observed between the fp group ( 44.8% ) and the xp group ( 54.2% ) . 
 similarly , no significant differences in median progression - free survival and median overall survival were observed between regimen groups . 
 multivariate analysis showed that poor performance status ( eastern cooperative oncology group [ ecog ] status2 ) , weight loss ( 10% of the weight loss for 3 months ) , low albumin level ( 3.5 g / dl ) , and absence of previous esophagectomy at the time of chemotherapy were significantly associated with low os in both groups ( p<0.05 ) . 
 based on these findings , patients were classified into favorable ( score , 0 to 90 ) , intermediate ( 91 - 134 ) , and poor ( > 135 ) prognostic groups . the median survival for those with a favorable ecog was 13.8 months ( 95% confidence interval [ ci ] , 10.8 to 18.6 months ) , for intermediate 11.2 months ( 95% ci , 8.7 to 11.9 months ) , and for poor , 7.0 months ( 95% ci , 3.6 to 10.0 months ) . 
 external validation of the nomogram in a different patient cohort yielded significantly similar findings.conclusionthe nomogram described here predicts survival in mescc patients and could serve as a guide for the use of fp / xp chemotherapy in mescc patients . 