Neoadjuvant Chemoradiotherapy and Surgery Versus Surgery Alone in Resectable Pancreatic Cancer: A Single-Center Prospective, Randomized, Controlled Trial Which Failed to Achieve Accrual Targets Oncological Benefits of Neoadjuvant Chemoradiation With Gemcitabine Versus Upfront Surgery in Patients With Borderline Resectable Pancreatic Cancer: A Prospective, Randomized, Open-label, Multicenter Phase 2/3 Trial Neoadjuvant chemoradiation therapy with gemcitabine/cisplatin and surgery versus immediate surgery in resectable pancreatic cancer Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial A Randomized Phase 2 Trial of Neoadjuvant Chemotherapy in Resectable Pancreatic Cancer: Gemcitabine Alone Versus Gemcitabine Combined with Cisplatin Impact of preoperative chemoradiotherapy on survival in patients with resectable pancreatic cancer. Prospective phase II trial of neoadjuvant chemotherapy with gemcitabine and cisplatin for resectable adenocarcinoma of the pancreatic head. A reappraisal of preoperative chemoradiation for localized pancreatic head ductal adenocarcinoma in a 5-year single-institution experience Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. Quantitative Synthesis in Systematic Reviews Preoperative gemcitabine and cisplatin followed by gemcitabine-based chemoradiation for resectable adenocarcinoma of the pancreatic head. Randomized phase III trial of adjuvant chemotherapy with gemcitabine versus S-1 in patients with resected pancreatic cancer: Japan Adjuvant Study Group of Pancreatic Cancer (JASPAC-01). Neoadjuvant Chemotherapy Generates a Significant Tumor Response in Resectable Pancreatic Cancer Without Increasing Morbidity: Results of a Prospective Phase II Trial Neoadjuvant Therapy is Associated with a Reduced Lymph Node Ratio in Patients with Potentially Resectable Pancreatic Cancer
Objective The objective of the study is to evaluate the usefulness of neoadjuvant chemoradiotherapy in resectable pancreatic cancer . Methods A single-center RCT of patients affected by resectable pancreatic adenocarcinoma which included arm A ( surgery alone ) and arm B ( neoadjuvant chemoradiation and surgery ) . The primary endpoint was R0 resection ; the secondary endpoints were toxicity ; number of patients who completed the neoadjuvant therapy ; radiological and pathological response after chemoradiation ; and pTNM stage , postoperative morbidity , mortality , and overall and disease-free survival .  A sample size of 32 patients was required for each group . Results The study was terminated early , and 38 patients were r and omized : 20 in arm A and 18 in arm B. There was no significant difference regarding R0 resection rate in the two groups ( intention-to-treat , OR = 1.91 , P = 0.489 ) . Neoadjuvant chemoradiotherapy was completed in 14 out of 18 cases ( 77.8 % ) and the radiological and pathological response was efficacious in 72.3 and 90.9 % of cases , respectively . Conclusions Neoadjuvant chemoradiation was feasible , safe , and efficacious , although non-significant results were obtained as a result of the underpowered data due to the difficulty in recruiting patients . Additional multicenter RCTs are needed in the future Objective : This study was performed to determine whether neoadjuvant treatment increases survival in patients with BRPC . Summary Background Data : Despite many promising retrospective data on the effect of neoadjuvant treatment for borderline resectable pancreatic cancer ( BRPC ) , no high-level evidence exists to support the role of such treatment . Methods : This phase 2/3 multicenter r and omized controlled trial was design ed to enroll 110 patients with BRPC who were r and omly assigned to gemcitabine-based neoadjuvant chemoradiation treatment ( 54 Gray external beam radiation ) followed by surgery or upfront surgery followed by chemoradiation treatment from four large-volume centers in Korea . The primary endpoint was the 2-year survival rate ( 2-YSR ) . Interim analysis was planned at the time of 50 % case enrollment . Results : After excluding the patients who withdrew consent ( n = 8) from the 58 enrolled patients , 27 patients were allocated to neoadjuvant treatment and 23 to upfront surgery groups . The overall 2-YSR was 34.0 % with a median survival of 16 months . In the intention-to-treat analysis , the 2-YSR and median survival were significantly better in the neoadjuvant chemoradiation than the upfront surgery group [ 40.7 % , 21 months vs 26.1 % , 12 months , hazard ratio 1.495 ( 95 % confidence interval 0.66–3.36 ) , P = 0.028 ] . R0 resection rate was also significantly higher in the neoadjuvant chemoradiation group than upfront surgery ( n = 14 , 51.8 % vs n = 6 , 26.1 % , P = 0.004 ) . The safety monitoring committee decided on early termination of the study on the basis of the statistical significance of neoadjuvant treatment efficacy . Conclusion : This is the first prospect i ve r and omized controlled trial on the oncological benefits of neoadjuvant treatment in BRPC . Compared to upfront surgery , neoadjuvant chemoradiation provides oncological benefits in patients with BRPC Background In nonr and omized trials , neoadjuvant treatment was reported to prolong survival in patients with pancreatic cancer . As neoadjuvant chemoradiation is established for the treatment of rectal cancer we examined the value of neoadjuvant chemoradiotherapy in pancreatic cancer in a r and omized phase II trial . Radiological staging defining resectability was basic information prior to r and omization in contrast to adjuvant therapy trials resting on pathological staging . Patients and methods Patients with resectable adenocarcinoma of the pancreatic head were r and omized to primary surgery ( Arm A ) or neoadjuvant chemoradiotherapy followed by surgery ( Arm B ) , which was followed by adjuvant chemotherapy  in both arms . A total of 254 patients were required to detect a 4.33-month improvement in median overall survival ( mOS ) . Results The trial was stopped after 73 patients ; 66 patients were eligible for analysis . Twenty nine of 33 allocated patients received chemoradiotherapy . Radiotherapy was completed in all patients . Chemotherapy was changed in 3 patients due to toxicity . Tumor resection was performed in 23 vs. 19 patients ( A vs. B ) . The R0 resection rate was 48 % ( A ) and 52 % ( B , P = 0.81 ) and (y)pN0 was 30 % ( A ) vs. 39 % ( B , P = 0.44 ) , respectively . Postoperative complications were comparable in both groups . mOS was 14.4 vs. 17.4 months ( A vs. B ; intention-to-treat analysis ; P = 0.96 ) . After tumor resection , mOS was 18.9 vs. 25.0 months ( A vs. B ; P = 0.79 ) . Conclusion This worldwide first r and omized trial for neoadjuvant chemoradiotherapy in pancreatic cancer showed that neoadjuvant chemoradiation is safe with respect to toxicity , perioperative morbidity , and mortality . Nevertheless , the trial was terminated early due to slow recruiting and the results were not significant . IS RCT N78805636 ; NCT00335543.ZusammenfassungHintergrundMehrere nichtr and omisierte Studien zeigten , dass eine neoadjuvante Therapie das Überleben bei Patienten mit Pankreaskarzinom verlängert . Beim lokal fortgeschrittenen Rektumkarzinom gehört die neoadjuvante Radiochemotherapie bereits zum Therapiest and ard . Analog wurde der Stellenwert einer Radiochemotherapie beim Pankreaskarzinom in einer r and omisierten Phase-II-Studie untersucht . Das prätherapeutische radiologische Staging war Grundlage dieser Studie i m Gegensatz zu adjuvanten Therapiestudien , die auf pathohistologischem Staging basieren . Patienten und Method enPatienten mit resektablem Pankreaskopfkarzinom wurden r and omisiert in primäre Operation ( Arm A ) versus neoadjuvante Radiochemotherapie gefolgt von einer Operation ( Arm B ) . Beide Gruppen erhielten eine adjuvante Chemotherapie . Es waren 254 Patienten erforderlich , um eine Verbesserung des medianen Gesamtüberlebens von 4,33 Monaten zu erfassen . ErgebnisseDie Studie wurde wegen zögerlicher Rekrutierung nach Einschluss von 73 Patienten beendet . Insgesamt konnten 66 Patienten ausgewertet werden . Die ihnen zugeordnete Radiochemotherapie erhielten 29 von 33 Patienten . Alle Patienten bekamen die vollständige Bestrahlungstherapie . Wegen der Toxizität wurde bei 3 Patienten die Chemotherapie reduziert . Eine Pankreastumorresektion erhielten 23 vs. 19 Patienten ( A vs. B ) . Die R0-Resektionsrate betrug 48 % ( A ) und 52 % ( B , P = 0,81 ) . Bei 30 % ( A ) versus 39 % ( B , P = 0,44 ) der resezierten Patienten waren keine Lymphknotenmetastasen vorh and en . Die postoperativen Komplikationen waren in beiden Gruppen vergleichbar . Das mediane Gesamtüberleben betrug 14,4 vs. 17,4 Monate ( A vs. B ; „ Intention-to-treat“-Analyse ; P = 0,96 ) . Nach Pankreastumorresektion stieg das Gesamtüberleben auf 18,9 vs. 25,0 Monate ( A vs. B ; P = 0,79).SchlussfolgerungDiese weltweit erste r and omisierte Studie zur neoadjuvanten Radiochemotherapie beim Pankreaskopfkarzinom war in Bezug auf Toxizität sowie perioperative Morbidität und Mortalität gut durchführbar . Die Ergebnisse sind jedoch nicht signifikant , da diese r and omisierte Studie vorzeitig wegen mangelnder Rekrutierung beendet werden musste . IS RCT N78805636 ; NCT00335543 BACKGROUND The role of adjuvant treatment in pancreatic cancer remains uncertain . The European Study Group for Pancreatic Cancer ( ESPAC ) assessed the roles of chemoradiotherapy and chemotherapy in a r and omised study . METHODS After resection , patients were r and omly assigned to adjuvant chemoradiotherapy ( 20 Gy in ten daily fractions over 2 weeks with 500 mg/m(2 ) fluorouracil intravenously on days 1 - 3 , repeated after 2 weeks ) or chemotherapy ( intravenous fluorouracil 425 mg/m(2 ) and folinic acid 20 mg/m(2 ) daily for 5 days , monthly for 6 months ) . Clinicians could r and omise patients into a two-by-two factorial design ( observation , chemoradiotherapy alone , chemotherapy alone , or both ) or into one of the main treatment comparisons ( chemoradiotherapy versus no chemoradiotherapy or chemotherapy versus no chemotherapy ) . The primary endpoint was death , and all analyses were by intention to treat . Findings 541 eligible patients with pancreatic ductal adenocarcinoma were r and omised : 285 in the two-by-two factorial design ( 70 chemoradiotherapy , 74 chemotherapy , 72 both , 69 observation ) ; a further 68 patients were r and omly assigned chemoradiotherapy or no chemoradiotherapy and 188 chemotherapy or no chemotherapy .  Median follow-up of the 227 ( 42 % ) patients still alive was 10 months ( range 0 - 62 ) . Overall results showed no benefit for adjuvant chemoradiotherapy ( median survival 15.5 months in 175 patients with chemoradiotherapy vs 16.1 months in 178 patients without ; hazard ratio 1.18 [ 95 % CI 0.90 - 1.55 ] , p=0.24 ) . There was evidence of a survival benefit for adjuvant chemotherapy ( median survival 19.7 months in 238 patients with chemotherapy vs 14.0 months in 235 patients without ; hazard ratio 0.66 [ 0.52 - 0.83 ] , p=0.0005 ) . Interpretation This study showed no survival benefit for adjuvant chemoradiotherapy but revealed a potential benefit for adjuvant chemotherapy , justifying further r and omised controlled trials of adjuvant chemotherapy in pancreatic cancer Background Survival after surgery for pancreas cancer remains low . This improves with adjuvant chemotherapy , but up to 30 % patients do not receive the prescribed treatment . Neoadjuvant therapy may increase the proportion of patients who receive all treatment components , may downstage disease before surgery , and may provide early treatment of micrometastases . This r and omized phase 2 study compares gemcitabine-based chemotherapy regimens to identify the most promising regimen for future study . Methods Fifty patients with potentially resectable pancreas lesions were enrolled onto the study . Twenty-four patients were r and omized to gemcitabine ( 1000 mg/m2 ) every 7 days for 43 days ; 26 patients were r and omized to gemcitabine ( 1000 mg/m2 ) and cisplatin ( 25 mg/m2 ) , 7 to the original schedule ( omitting day 22 ) and 19 to a revised schedule due to neutropenia ( omitting days 15 and 36 ) . The primary outcome measure was resection rate . Results Patients who were allocated to gemcitabine received a median of 85 % of the planned dose . Patients who were allocated to combination treatment received a median of 88 % and 92 % of the planned gemcitabine and cisplatin doses , respectively . There were 10 episodes of grade III/IV hematological toxicity in each group . Twenty-seven patients ( 54 % ) underwent pancreatic resection , 9 ( 38 % ) in the gemcitabine arm and 18 ( 70 % ) in the combination arm , with no increase in surgical complications . To date , 34 patients ( 68 % ) have died . Twelve-month survival for the gemcitabine and combination groups was 42 % and 62 % . Conclusions Chemotherapy can be safely administered before pancreatic surgery . Combination therapy with gemcitabine and cisplatin is associated with a high resection rate and an encouraging survival rate , suggesting that further study is warranted AIM To explore whether preoperative chemoradiation therapy improves survival of patients with pancreatic cancer undergoing resectional surgery .  METHODS Forty-seven patients with a malignant pancreatic tumor localized in the head or uncinate process of the pancreas underwent radical pancreatico-duodenectomy .  Twenty-two received chemoradiation therapy ( gemcitabine and radiation dose 50.4 Gy ) before surgery ( CRR ) and 25 patients underwent surgery only ( RO ) . The study was non-r and omised . Patients were identified from a prospect i ve data base . RESULTS The median survival time was 30.2 mo in the CRR group and 35.9 mo in the RO group . No statistically significant differences were found in subclasses according to lymph node involvement , TNM stages , tumor size , or perineural invasion . The one , three and five year survival rates were 81 % , 33 % and 33 % , respectively , in the CRR group and 72 % , 47 % and 23 % , respectively , in the RO group . In ductal adenocarcinoma , the median survival time was 27 mo in the CRR group and 20 mo in the RO group . No statistically significant differences were found in the above subclasses . The one , three and five year survival rates were 79 % , 21 % and 21 % , respectively , in the CRR group and 64 % , 50 % and 14 % , respectively , in the RO group . The overall hospital mortality rate was 2 % . The morbidity rate was 45 % in the CRR group and 32 % ( NS ) in the RO group . CONCLUSION Major multicenter r and omized studies are needed to conclusively assess the impact of neoadjuvant treatment in the management of pancreatic cancer PURPOSE To test the safety of neoadjuvant chemotherapy for resectable pancreatic cancer . PATIENTS AND METHODS Patients with cytologically proven resectable adenocarcinoma of the pancreatic head were eligible for this prospect i ve phase II trial . After confirmation of resectability by contrast-enhanced computed tomography ( ceCT ) , positron emission tomography/CT , laparoscopy , and endoscopic ultrasound , patients received four biweekly cycles of gemcitabine 1,000 mg/m(2 ) and cisplatin 50 mg/m(2 ) . Thereafter , staging was repeated and patients underwent surgery .  Quality of life ( QoL ) and prealbumin serum levels were determined pre- and postchemotherapy . Follow-up included 3-month CA 19 - 9 measurements and ceCT after 6 , 12 , 18 , and 24 months . Histologic tumor response was assessed by two scoring systems . RESULTS Twenty-eight patients entered this study .  Adverse effects were mainly gastrointestinal and hematologic , most often mild , and never of grade 4 . Twenty-six patients ( 93 % ) had resectable cancer on restaging examinations , and the R0 resection rate was 80 % . Histologic tumor response and cytopathic effects were documented in 54 % and 83 % of patients , respectively . On intention-to-treat analysis , disease-free and overall survival were 9.2 months ( 95 % CI , 5.6 to 12.9 months ) and 26.5 months ( 95 % CI , 11.4 to 41.5 months ) and 9 months ( 95 % CI , 6.99 to 10.1 months ) and 19.1 months ( 95 % CI , 15 to 23.1 months ) for ductal adenocarcinoma , respectively . QoL improved in two items and was unchanged in all other items . Moreover , prealbumin serum levels significantly improved during chemotherapy ( P = .008 ) . CONCLUSION Neoadjuvant chemotherapy with gemcitabine and cisplatin is well tolerated and does not impair resectability of pancreatic cancer . Furthermore , it improves the QoL and the nutritional status of affected patients with favorable overall and disease-free survival Resection of localized pancreatic head ductal adenocarcinoma ( LPHDA ) has a limited impact on survival . Mechanisms of improvement provided by preoperative chemoradiation therapy ( CRT ) remain under debate . This study analyzes the outcome of patients treated for LPHDA to delineate the benefits of CRT . Among 87 patients with LPHDA , 17 had a pancreaticoduodenectomy alone ( group I ) . Thirtynine with initially resectable cancers received CRT with 5-fluorouracil-based chemotherapy ( group II ) . Thirty-one with initially unresectable cancers were similarly treated by CRT ( group III ) . Patients in groups II and III were restaged after completion of CRT . In patients with resectable disease , resection was planned . Patients in groups I and II were statistically comparable in terms of age , sex , and pretherapeutic stage . Median survival and 2-year overall survival in group I were 13.7 months and 31 % , respectively . In group II , 23 patients ( 59 % ) had a pancreaticoduodenectomy ( group IIa ) and 16 patients ( 41 % ) did not have resection ( group IIb ) . Median survival and 2-year overall survival were as follows : group IIa , 26.6 months and 51 % ; and group IIb , 6.1 months and 0 % , respectively . In group IIa , pathologic examination revealed eight major responses ( 35 % ) including two sterilized specimens , and none of the patients had locoregional recurrence . In group III , none of the patients had resection , and median survival was 8 months with one 2-year survivor . Patient selection appears to play a major role with regard to results achieved with preoperative CRT followed by pancreaticoduodenectomy . However , a high histologic response rate and excellent local control can also be achieved IMPORTANCE The prognosis for patients with pancreatic cancer is poor , even after resection with curative intent . Gemcitabine-based chemotherapy is st and ard treatment for advanced pancreatic cancer , but its effect on survival in the adjuvant setting has not been demonstrated . OBJECTIVE To analyze whether previously reported improvement in disease-free survival with adjuvant gemcitabine therapy translates into improved overall survival . DESIGN , SETTING , AND PATIENTS CONKO-001 ( Charité Onkologie 001 ) , a multicenter , open-label , phase 3 r and omized trial to evaluate the efficacy and toxicity of gemcitabine in patients with pancreatic cancer after complete tumor resection . Patients with macroscopically completely removed pancreatic cancer entered the study between July 1998 and December 2004 in 88 hospitals in Germany and Austria . Follow-up ended in September 2012 . INTERVENTIONS After stratification for tumor stage , nodal status , and resection status , patients were r and omly assigned to either adjuvant gemcitabine treatment ( 1g/m2 d 1 , 8 , 15 , q 4 weeks ) for 6 months or to observation alone . MAIN OUTCOMES AND MEASURES The primary end point was disease-free survival . Secondary end points included treatment safety and overall survival , with overall survival defined as the time from date of r and omization to death . Patients lost to follow-up were censored on the date of their last follow-up . RESULTS A total of 368 patients were r and omized , and 354 were eligible for intention-to-treat- analysis . By September 2012 , 308 patients ( 87.0 % [ 95 % CI , 83.1%-90.1 % ] ) had relapsed and 316 patients ( 89.3 % [ 95 % CI , 85.6%-92.1 % ] ) had died . The median follow-up time was 136 months . The median disease-free survival was 13.4 ( 95 % CI , 11.6 - 15.3 ) months in the treatment group compared with 6.7 ( 95 % CI , 6.0 - 7.5 ) months in the observation group ( hazard ratio , 0.55 [ 95 % CI , 0.44 - 0.69 ] ; P < .001 ) . Patients r and omized to adjuvant gemcitabine treatment had prolonged overall survival compared with those r and omized to observation alone ( hazard ratio , 0.76 [ 95 % CI , 0.61 - 0.95 ] ; P = .01 ) , with 5-year overall survival of 20.7 % ( 95 % CI , 14.7%-26.6 % ) vs 10.4 % ( 95 % CI , 5.9%-15.0 % ) , respectively , and 10-year overall survival of 12.2 % ( 95 % CI , 7.3%-17.2 % ) vs 7.7 % ( 95 % CI , 3.6%-11.8 % ) . CONCLUSIONS AND RELEVANCE Among patients with macroscopic complete removal of pancreatic cancer , the use of adjuvant gemcitabine for 6 months compared with observation alone result ed in increased overall survival as well as disease-free survival . These findings provide strong support for the use of gemcitabine in this setting . TRIAL REGISTRATION is rct n.org Identifier : IS RCT N34802808 BACKGROUND The effect of adjuvant treatment on survival in pancreatic cancer is unclear . We report the final results of the European Study Group for Pancreatic Cancer 1 Trial and up date the interim results . METHODS In a multicenter trial using a two-by-two factorial design , we r and omly assigned 73 patients with resected pancreatic ductal adenocarcinoma to treatment with chemoradiotherapy alone ( 20 Gy over a two-week period plus fluorouracil ) , 75 patients to chemotherapy alone ( fluorouracil ) , 72 patients to both chemoradiotherapy and chemotherapy , and 69 patients to observation .  RESULTS The analysis was based on 237 deaths among the 289 patients ( 82 percent ) and a median follow-up of 47 months ( interquartile range , 33 to 62 ) . The estimated five-year survival rate was 10 percent among patients assigned to receive chemoradiotherapy and 20 percent among patients who did not receive chemoradiotherapy ( P=0.05 ) . The five-year survival rate was 21 percent among patients who received chemotherapy and 8 percent among patients who did not receive chemotherapy ( P=0.009 ) . The benefit of chemotherapy persisted after adjustment for major prognostic factors . CONCLUSIONS Adjuvant chemotherapy has a significant survival benefit in patients with resected pancreatic cancer , whereas adjuvant chemoradiotherapy has a deleterious effect on survival A quantitative systematic review , or meta- analysis , uses statistical methods to combine the results of multiple studies . Meta-analyses have been done for systematic review s of therapeutic trials , diagnostic test evaluations , and epidemiologic studies . Although the statistical methods involved may at first appear to be mathematically complex , their purpose is simple : They are trying to answer four basic questions . Are the results of the different studies similar ? To the extent that they are similar , what is the best overall estimate ? How precise and robust is this estimate ? Finally , can dissimilarities be explained ? This article provides some guidance in underst and ing the key technical aspects of the quantitative approach to these questions . We have avoided using equations and statistical notations ; interested readers will find implementations of the described methods in the listed references . We focus here on the quantitative synthesis of reports of r and omized , controlled , therapeutic trials because far more meta-analyses on therapeutic studies than on other types of studies have been published . For practical reasons , we present a stepwise description of the tasks that are performed when statistical methods are used to combine data . These tasks are 1 ) deciding whether to combine data and defining what to combine , 2 ) evaluating the statistical heterogeneity of the data , 3 ) estimating a common effect , 4 ) exploring and explaining heterogeneity , 5 ) assessing the potential for bias , and 6 ) presenting the results . Deciding Whether To Combine Data and Defining What To Combine By the time one performs a quantitative synthesis , certain decisions should already have been made about the formulation of the question and the selection of included studies . These topics were discussed in two previous articles in this series [ 1 , 2 ] . Statistical tests can not compensate for lack of common sense , clinical acumen , and biological plausibility in the design of the protocol of a meta- analysis . Thus , a reader of a systematic review should always address these issues before evaluating the statistical methods that have been used and the results that have been generated . Combining poor- quality data , overly biased data , or data that do not make sense can easily produce unreliable results . The data to be combined in a meta- analysis are usually either binary or continuous . Binary data involve a yes/no categorization ( for example , death or survival ) . Continuous data take a range of values ( for example , change in diastolic blood pressure after antihypertensive treatment , measured in mm Hg ) . When one is comparing groups of patients , binary data can be summarized by using several measures of treatment effect that were discussed earlier in this series [ 3 ] . These measures include the risk ratio ; the odds ratio ; the risk difference ; and , when study duration is important , the incidence rate . Another useful clinical measure , the number needed to treat ( NNT ) , is derived from the inverse of the risk difference [ 3 ] . Treatment effect measures , such as the risk ratio and the odds ratio , provide an estimate of the relative efficacy of an intervention , whereas the risk difference describes the intervention 's absolute benefit . The various measures of treatment effect offer complementary information , and all should be examined [ 4 ] . Continuous data can be summarized by the raw mean difference between the treatment and control groups when the treatment effect is measured on the same scale ( for example , diastolic blood pressure in mm Hg ) , by the st and ardized mean difference when different scales are used to measure the same treatment effect ( for example , different pain scales being combined ) , or by the correlation coefficients between two continuous variables [ 5 ] . The st and ardized mean difference , also called the effect size , is obtained by dividing the difference between the mean in the treatment group and the mean in the control group by the SD in the control group . Evaluating the Statistical Heterogeneity of the Data This step is intended to answer the question , Are the results of the different studies similar ( homogeneous ) ? It is important to answer this question before combining any data . To do this , one must calculate the magnitude of the statistical diversity ( heterogeneity ) of the treatment effect that exists among the different sets of data . Statistical diversity can be thought of as attributable to one or both of two causes . First , study results can differ because of r and om sampling error . Even if the true effect is the same in each study , the results of different studies would be expected to vary r and omly around the true common fixed effect . This diversity is called the within- study variance . Second , each study may have been drawn from a different population , depending on the particular patients chosen and the interventions and conditions unique to the study . Therefore , even if each study enrolled a large patient sample , the treatment effect would be expected to differ . These differences , called r and om effects , describe the between- study variation with regard to an overall mean of the effects of all of the studies that could be undertaken . The test most commonly used to assess the statistical significance of between- study heterogeneity is based on the chi-square distribution [ 6 ] . It provides a measure of the sum of the squared differences between the results observed and the results expected in each study , under the assumption that each study estimates the same common treatment effect . A large total deviation indicates that a single common treatment effect is unlikely . Any pooled estimate calculated must account for the between- study heterogeneity . In practice , this test has low sensitivity for detecting heterogeneity , and it has been suggested that a liberal significance level , such as 0.1 , should be used [ 6 ] . Estimating a Common Effect The questions that this step tries to answers are , 1 ) To the extent that data are similar , what is their best common point estimate of a therapeutic effect , and 2 ) how precise is this estimate ? The mathematical process involved in this step generally involves combining ( pooling ) the results of different studies into an overall estimate . Compared with the results of individual studies , pooled results can increase statistical power and lead to more precise estimates of treatment effect . Each study is given a weight according to the precision of its results . The rationale is that studies with narrow CIs should be weighted more heavily than studies with greater uncertainty . The precision is generally expressed by the inverse of the variance of the estimate of each study . The variance has two components : the variance of the individual study and the variance between different studies . When the between- study variance is found to be or assumed to be zero , each study is simply weighted by the inverse of its own variance , which is a function of the study size and the number of events in the study . This approach characterizes a fixed-effects model , as exemplified by the Mantel-Haenszel method [ 7 , 8 ] or the Peto method [ 9 ] for dichotomous data . The Peto method has been particularly popular in the past . It has the advantage of simple calculation ; however , although it is appropriate in most cases , it may introduce large biases if the data are unbalanced [ 10 , 11 ] . On the other h and , r and om-effects models also add the between- study variance to the within- study variance of each individual study when the pooled mean of the r and om effects is calculated . The r and om-effects model most commonly used for dichotomous data is the DerSimonian and Laird estimate of the between- study variance [ 12 ] . Fixed- and r and om-effects models for continuous data have also been described [ 13 ] . Pooled results are generally reported as a point estimate and CI , typically a 95 % CI . Other quantitative techniques for combining data , such as the Confidence Profile Method [ 14 ] , use Bayesian methods to calculate posterior probability distributions for effects of interest . Bayesian statistics are based on the principle that each observation or set of observations should be viewed in conjunction with a prior probability describing the prior knowledge about the phenomenon of interest [ 15 ] . The new observations alter this prior probability to generate a posterior probability . Traditional meta- analysis assumes that nothing is known about the magnitude of the treatment effect before r and omized trials are performed . In Bayesian terms , the prior probability distribution is noninformative . Bayesian approaches may also allow the incorporation of indirect evidence in generating prior distributions [ 14 ] and may be particularly helpful in situations in which few data from r and omized studies exist [ 16 ] . Bayesian analyses may also be used to account for the uncertainty introduced by estimating the between- study variance in the r and om-effects model , leading to more appropriate estimates and predictions of treatment efficacy [ 17 ] . Exploring and Explaining Heterogeneity The next important issue is whether the common estimate obtained in the previous step is robust . Sensitivity analyses determine whether the common estimate is influenced by changes in the assumptions and in the protocol for combining the data . A comparison of the results of fixed- and r and om-effects models is one such sensitivity analysis [ 18 ] . Generally , the r and om-effects model produces wider CIs than does the fixed-effects model , and the level of statistical significance may therefore be different depending on the model used . The pooled point estimate per se is less likely to be affected , although exceptions are possible [ 19 ] . Other sensitivity analyses may include the examination of the residuals and the chi-square components [ 13 ] and assessment of the effect of deleting each study in turn . Statistically significant results that depend on a single study may require further exploration . Cumulative Meta- Analysis PURPOSE We conducted a phase II trial of preoperative gemcitabine and cisplatin chemotherapy in addition to chemoradiation ( Gem-Cis-XRT ) and pancreaticoduodenectomy ( PD ) for patients with stage I/II pancreatic adenocarcinoma . PATIENTS AND METHODS Chemotherapy consisted of gemcitabine ( 750 mg/m(2 ) ) and cisplatin ( 30 mg/m(2 ) ) given every 2 weeks for four doses . Chemoradiation consisted of four weekly infusions of gemcitabine ( 400 mg/m(2 ) ) combined with radiation therapy ( 30 Gy in 10 fractions administered over 2 weeks ) delivered 5 days per week . Patients underwent restaging 4 to 6 weeks after completion of chemoradiation and , in the absence of disease progression , were taken to surgery . RESULTS The study enrolled 90 patients ; 79 patients ( 88 % ) completed chemo-chemoradiation . Sixty-two ( 78 % ) of 79 patients were taken to surgery and 52 ( 66 % ) of 79 underwent PD . The median overall survival of all 90 patients was 17.4 months . Median survival for the 79 patients who completed chemo-chemoradiation was 18.7 months , with a median survival of 31 months for the 52 patients who underwent PD and 10.5 months for the 27 patients who did not undergo surgical resection of their primary tumor ( P < .001 ) . CONCLUSION Preoperative Gem-Cis-XRT did not improve survival beyond that achieved with preoperative gemcitabine-based chemoradiation ( Gem-XRT ) alone . The longer preoperative interval required more durable biliary decompression ( metal stents ) but was not associated with local tumor progression . The gemcitabine-based chemoradiation platform is a reasonable foundation on which to build future phase II multimodality trials for stage I/II pancreatic cancer incorporating emerging systemic therapies A r and omized controlled trial has begun in Japan to compare orally administered S-1 with intravenous gemcitabine ( GEM ) as adjuvant chemotherapy for patients with curatively resected pancreatic cancer . Patients are enrolled within 10 weeks after pancreatectomy to be treated for six months after assignment to either S-1 ( 80 mg/m(2)/day for four weeks , repeated similarly every six weeks for a total of four courses ) or GEM ( 1000 mg/m(2 ) on days 1 , 8 and 15 , repeated similarly every four weeks for a total of six courses ) . The primary endpoint is overall survival ; secondary endpoints include relapse-free survival , incidence of adverse events and health-related quality of life .  Each treatment arm includes 180 patients , providing an expected hazard ratio of 0.87 and an upper margin of 1.25 ( two-sided alpha-error , 0.05 ; power , 0.8 ) . Follow-up abdominal computed tomography is repeated every three months during the first two years , then every six months for three years Objective : To evaluate the morbidity of pancreaticoduodenectomy after neoadjuvant chemotherapy for resectable pancreatic cancer and to assess its histologic and metabolic response . Background : Adjuvant chemotherapy improves the outcome of pancreatic cancer , but 25 % of patients remain unfit after surgery . Neoadjuvant chemotherapy can be offered to all patients in a multimodality approach , but its efficacy and surgical morbidity are unknown . Methods : Patients with resectable , cytologically proven adenocarcinoma of the pancreatic head received 4 bi-weekly cycles of gemcitabine ( 1000 mg/m2 ) and cisplatin ( 50 mg/m2 ) in this prospect i ve phase II trial . Staging and restaging included chest x-ray , abdominal computed tomography ( CT ) , positron emission tomography (PET)/CT , endoscopic ultrasound , and laparoscopy . Fluorodeoxyglucose uptake was quantified by the st and ard-uptake value ( SUV ) on baseline and restaging PET/CT . Immunohistochemistry for GLUT-1 and Ki-67 was performed . The histologic response , cytopathic effects , and surgical complications were grade d by respective scores . Results : Twenty-four of 28 patients had resection for histologically confirmed adenocarcinoma . The surgical morbidity was low without perioperative death and one pancreatic fistula . Histologic response was documented in 54 % and cytopathic effects in 83 % of the patients . A significant SUV decrease occurred during chemotherapy ( P = 0.031 ) , which correlated with the baseline SUV ( P = 0.001 ) , Ki-67 expression ( P = 0.016 ) , and histologic response ( P = 0.01 ) . Neither the metabolic nor the histologic response was predictive of the median disease-free ( 9.2 months ) or overall survival ( 26.5 months ) . Conclusion : Neoadjuvant chemotherapy induced a significant metabolic and histologic response , which was best predicted by PET . Most importantly , surgery after neoadjuvant chemotherapy for pancreatic cancer was safe Abstract Background The use of neoadjuvant therapy ( NAC ) for the treatment of potentially resectable pancreatic cancer remains controversial . In this study , we sought to evaluate cancer-specific endpoints in patients undergoing a NAC versus a surgery-first ( SF ) approach with specific emphasis on lymph node metastases . Methods A total of 222 patients who underwent NAC and 85 patients who underwent SF were identified from 1990 to 2008 and compared for cancer-related endpoints . Peripancreatic lymph nodes from 135 neoadjuvant therapy patients were evaluated for histologic tumor regression . Results Patients who underwent NAC followed by surgery had improved overall survival and time to local recurrence compared with the SF approach . NAC patients were less likely to have lymph node metastases ( p = 0.001 ) , lymphovascular invasion ( LVI ) , and had smaller tumors . On multivariate analysis , lymph node positivity was associated with SF , tumor size , and the presence of LVI . NAC patients with N0 disease had equivalent outcomes to patients with a low-LNR ( 0.01–0.15 ) , whereas patients with a LNR > 0.15 had reduced survival , and time to local and distant recurrence . Ten of 135 ( 7.4 % ) NAC patients had evidence of tumor regression in at least one lymph node . Conclusions Patients with potentially resectable PDAC selected to undergo NAC  had improved survival and longer time to recurrence . Although some of these differences may be related to improvements in multimodality therapy completion rates , tumor regression in lymph node metastases exists and may demonstrate a biologic benefit of NAC compared with a SF approach
Objective The role of neoadjuvant therapy ( NAT ) in resectable pancreatic cancer ( RPC ) remains controversial .
Therefore , this meta- analysis was performed to compare the clinical differences between NAT and upfront surgery in RPC .