Efficacy of preoperative radiochemotherapy in patients with locally advanced pancreatic carcinoma Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group. Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection. Analysis of fluorouracil-based adjuvant chemotherapy and radiation after pancreaticoduodenectomy for ductal adenocarcinoma of the pancreas: results of a large, prospectively collected database at the Johns Hopkins Hospital. A randomised phase III trial comparing gemcitabine with surgery-only in patients with resected pancreatic cancer: Japanese Study Group of Adjuvant Therapy for Pancreatic Cancer Open-label, multicenter, randomized phase III trial of adjuvant chemoradiation plus interferon Alfa-2b versus fluorouracil and folinic acid for patients with resected pancreatic adenocarcinoma. Preoperative gemcitabine-based chemoradiation for patients with resectable adenocarcinoma of the pancreatic head. Pancreaticoduodenectomy for pancreatic adenocarcinoma: postoperative adjuvant chemoradiation improves survival. A prospective, single-institution experience. Preoperative versus postoperative chemoradiation for patients with resected pancreatic adenocarcinoma. 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. Further evidence of effective adjuvant combined radiation and chemotherapy following curative resection of pancreatic cancer Adjuvant gemcitabine alone versus gemcitabine-based chemoradiotherapy after curative resection for pancreatic cancer: a randomized EORTC-40013-22012/FFCD-9203/GERCOR phase II study. Chemoradiotherapy in the Treatment of Regional Pancreatic Carcinoma: A Phase II Study Prospective phase II trial of neoadjuvant chemotherapy with gemcitabine and cisplatin for resectable adenocarcinoma of the pancreatic head. Preoperative chemoradiation in adenocarcinoma of the pancreas. A single centre experience advocating a new treatment strategy. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. Preoperative gemcitabine and cisplatin followed by gemcitabine-based chemoradiation for resectable adenocarcinoma of the pancreatic head. Survival advantage of combined chemoradiotherapy compared with resection as the initial treatment of patients with regional pancreatic carcinoma Adjuvant Intra-Arterial Chemotherapy and Radiotherapy Versus Surgery Alone in Resectable Pancreatic and Periampullary Cancer: A Prospective Randomized Controlled Trial Surgery versus radiochemotherapy for resectable locally invasive pancreatic cancer: Final results of a randomized multi-institutional trial
Background . The optimal care for patients with unresectable , non-metastatic pancreatic adenocarcinoma ( PAC ) is debated . We treated 17 consecutive cases with preoperative radiochemotherapy ( RCT ) as a means for downstaging their tumours and compared outcome with 35 patients undergoing direct surgery for primarily resectable PAC during the same time period . Methods . The patients had biopsy proven , unresectable , non-metastatic PAC which engaged ≥50 % of the circumference of a patent mesenteric/portal vein for a distance ≥2 cm and /or < 50 % of the circumference of a central artery for < 2 cm . The preop therapy included two courses of Xelox ( oxaliplatin 130 mg/m2 d1 ; capecitabine 2 000 mg/m2 d1–14 q 3 w ) followed by 3-D conformal radiotherapy ( 50.4 Gy ; 1.8 Gy fractions ) with reduced Xelox ( d1 - 5 q 1 w X 6 ) . Results . No incident of RCT -related CTC Grade 3–4 haematologic and six cases of non-haematologic side-effects were diagnosed . Sixteen patients completed the RCT and were rescanned with CT and reevaluated for surgery 4 weeks post- RCT . Five cases were diagnosed with new metastases to the liver . Eleven patients were accepted for surgery whereof eight underwent a curative R0-resection . The median overall survival for the latter group was 29 months , which compared favourably with our control group of patients undergoing direct curative surgery for primarily resectable PAC ( median OS : 16 months ; RO-rate : 75 % ) . Perioperative morbidity was similar in the two cohorts but the duration of surgery was longer ( 576 vs. 477 min ) and the op blood loss was greater ( 3288 vs. 1460 ml ) in the RCT -cohort ( p < 0.05 ) . The 30-day mortality was zero in both groups . Conclusion . Preoperative RCT in patients with locally advanced PAC result ed in a high rate of curative resections and promising median survival in our treatment series . This trimodality approach merits further exploration in new studies , which are currently underway at our Department CONTEXT Among patients with locally advanced metastatic pancreatic adenocarcinoma , gemcitabine has been shown to improve outcomes compared with fluorouracil . OBJECTIVE To determine if the addition of gemcitabine to adjuvant fluorouracil chemoradiation ( chemotherapy plus radiation ) improves survival for patients with resected pancreatic adenocarcinoma . DESIGN , SETTING , AND PARTICIPANTS R and omized controlled phase 3 trial of patients with complete gross total resection of pancreatic adenocarcinoma and no prior radiation or chemotherapy enrolled between July 1998 and July 2002 with follow-up through August 18 , 2006 , at 164 US and Canadian institutions . INTERVENTION Chemotherapy with either fluorouracil ( continuous infusion of 250 mg/m2 per day ; n = 230 ) or gemcitabine ( 30-minute infusion of 1000 mg/m2 once per week ; n = 221 ) for 3 weeks prior to chemoradiation therapy and for 12 weeks after chemoradiation therapy . Chemoradiation with a continuous infusion of fluorouracil ( 250 mg/m2 per day ) was the same for all patients ( 50.4 Gy ) . MAIN OUTCOME MEASURES Survival for all patients and survival for patients with pancreatic head tumors  were the primary end points . Secondary end points included toxicity . RESULTS A total of 451 patients were r and omized , eligible , and analyzable . Patients with pancreatic head tumors ( n = 388 ) had a median survival of 20.5 months and a 3-year survival of 31 % in the gemcitabine group vs a median survival of 16.9 months and a 3-year survival of 22 % in the fluorouracil group ( hazard ratio , 0.82 [ 95 % confidence interval , 0.65 - 1.03 ] ; P = .09 ) . The treatment effect was strengthened on multivariate analysis ( hazard ratio , 0.80 [ 95 % confidence interval , 0.63 - 1.00 ] ; P = .05 ) . Grade 4 hematologic toxicity was 1 % in the fluorouracil group and 14 % in the gemcitabine group ( P < .001 ) without a difference in febrile neutropenia or infection . There were no differences in the ability to complete chemotherapy or radiation therapy ( > 85 % ) . CONCLUSIONS The addition of gemcitabine to adjuvant fluorouracil-based chemoradiation was associated with a survival benefit for patients with resected pancreatic cancer , although this improvement was not statistically significant . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00003216 OBJECTIVE The survival benefit of adjuvant radiotherapy and 5-fluorouracil versus observation alone after surgery was investigated in patients with pancreatic head and periampullary cancers . SUMMARY BACKGROUND DATA A previous study of adjuvant radiotherapy and chemotherapy in these cancers by the Gastrointestinal Tract Cancer Cooperative Group of EORTC has been followed by other studies with conflicting results . METHODS Eligible patients with T1 - 2N0 - 1aM0 pancreatic head or T1 - 3N0 - 1aM0 periampullary cancer and histologically proven adenocarcinoma were r and omized after resection . RESULTS Between 1987 and 1995 , 218 patients were r and omized ( 108 patients in the observation group , 110 patients in the treatment group ) . Eleven patients were ineligible ( five in the observation group and six in the treatment group ) . Baseline characteristics were comparable between the two groups . One hundred fourteen patients ( 55 % ) had pancreatic cancer ( 54 in the observation group and 60 in the treatment group ) . In the treatment arm , 21 patients ( 20 % ) received no treatment because of postoperative complications or patient refusal . In the treatment group , only minor toxicity was observed . The median duration of survival was 19.0 months for the observation group and 24.5 months in the treatment group ( log-rank , p = 0.208 ) . The 2-year survival estimates were 41 % and 51 % , respectively . The results when stratifying for tumor location showed a 2-year survival rate of 26 % in the observation group and 34 % in the treatment group ( log-rank , p = 0.099 ) in pancreatic head cancer ; in periampullary cancer , the 2-year survival rate was 63 % in the observation group and 67 % in the treatment group ( log-rank , p = 0.737 ) . No reduction of locoregional recurrence rates was apparent in the groups . CONCLUSIONS Adjuvant radiotherapy in combination with 5-fluorouracil is safe and well tolerated . However , the benefit in this study was small ; routine use of adjuvant chemoradiotherapy is not warranted as st and ard treatment in cancer of the head of the pancreas or periampullary region The efficacy of combined radiation and fluorouracil as adjuvant therapy for pancreatic cancer is suggested by a prospect i ve r and omized study conducted by the Gastrointestinal Tumor Study Group ( GITSG ) . Twenty-two patients r and omized to no adjuvant treatment and 21 to combined therapy were analyzed . Neither life-threatening toxic reaction nor death due to toxic effect was encountered . The study was terminated prematurely because of an unacceptably low rate of accrual combined with the observation of increasingly large survival differences between the study arms . Median survival for the treatment group ( 20 months ) was significantly longer than that observed for the control group ( 11 months ) . Four patients , three in the treated and one in the control group , have survived five years or longer following surgery . The extent of the tumor and initial performance status were significantly and independently related to survival PURPOSE To examine the efficacy of adjuvant chemoradiotherapy after pancreaticoduodenectomy ( PD ) for pancreatic adenocarcinoma ( PC ) in patients undergoing resection at Johns Hopkins Hospital ( JHH ; Baltimore , MD ) . PATIENTS AND METHODS Between August 30 , 1993 , and February 28 , 2005 , a total of 908 patients underwent PD for PC at JHH . A prospect i ve data base was review ed to determine which patients received fluorouracil ( FU ) -based CRT .  Excluded patients had metastatic disease , died 60 or fewer days after PD , received preoperative therapy , an experimental vaccine , adjuvant chemotherapy or radiation alone . The final cohort includes 616 patients . RESULTS The median follow-up was 17.8 months ( interquartile range , 9.7 to 33.5 months ) . Overall median survival was 17.9 months ( 95 % CI , 16.3 to 19.5 months ) . Groups were similar with respect to tumor size , nodal status , and margin status , but the CRT group was younger ( P < .001 ) , and less likely to present with a severe comorbid disease ( P = .001 ) . Patients with carcinomas larger than 3 cm ( P = .001 ) , grade 3 and 4 ( P < .001 ) , margin-positive resection ( P = .001 ) , and complications after surgery ( P = .017 ) had poor long-term survival . Patients receiving CRT experienced an improved median ( 21.2 v 14.4 months ; P < .001 ) , 2-year ( 43.9 % v 31.9 % ) , and 5-year ( 20.1 % v 15.4 % ) survival compared with no CRT . After controlling for high-risk features , CRT was still associated with improved survival ( relative risk = 0.74 ; 95 % CI , 0.62 to 0.89 ) . CONCLUSION These data suggest that adjuvant concurrent FU-based CRT significantly improves survival after PD for PC when compared with patients not receiving CRT . These data support the use of combined adjuvant CRT for PC Background : This multicentre r and omised phase III trial was design ed to determine whether adjuvant chemotherapy with gemcitabine improves the outcomes of patients with resected pancreatic cancer . Methods : Eligibility criteria included macroscopically curative resection of invasive ductal carcinoma of the pancreas and no earlier radiation or chemotherapy . Patients were r and omly assigned at a 1 : 1 ratio to either the gemcitabine group or the surgery-only group . Patients assigned to the gemcitabine group received gemcitabine at a dose of 1000 mg m−2 over 30 min on days 1 , 8 and 15 , every 4 weeks for 3 cycles . Results : Between April 2002 and March 2005 , 119 patients were enrolled in this study . Among them , 118 were eligible and analysable ( 58 in the gemcitabine group and 60 in the surgery-only group ) . Both groups were well balanced in terms of baseline characteristics . Although heamatological toxicity was frequently observed in the gemcitabine group , most toxicities were transient , and grade 3 or 4 non-heamatological toxicity was rare . Patients in the gemcitabine group showed significantly longer disease-free survival ( DFS ) than those in the surgery-only group ( median DFS , 11.4versus 5.0 months ; hazard ratio=0.60 ( 95 % confidence interval ( CI ) : 0.40–0.89 ) ; P=0.01 ) , although overall survival did not differ significantly between the gemcitabine and surgery-only groups ( median overall survival , 22.3 versus 18.4 months ; hazard ratio=0.77 ( 95 % CI : 0.51–1.14 ) ; P=0.19 ) . Conclusion : The current results suggest that adjuvant gemcitabine contributes to prolonged DFS in patients undergoing macroscopically curative resection of pancreatic cancer PURPOSE Adjuvant chemotherapy prolongs survival in patients with pancreatic cancer , but its benefit is limited . Long-term survival times of up to 44 months after adjuvant chemoradioimmunotherapy in phase II trials motivated the present study . PATIENTS AND METHODS Between 2004 and 2007 , 132 R0/R1 resected patients received either fluorouracil ( FU ) , cisplatin , and interferon alfa-2b ( IFN α-2b ) plus radiotherapy followed by two cycles of FU ( arm A , n=64 ) or six cycles of FU monotherapy ( arm B , n=68 ) . One hundred ten patients ( arm A , n=53 ; arm B , n=57 ) received at least one dose of the study medication , and these patients composed the per- protocol ( PP ) population . Biomarkers were analyzed longitudinally for their predictive value . RESULTS Median survival for all r and omly assigned patients was 26.5 months ( 95 % CI , 21.6 to 39.5 months ) in arm A and 28.5 months ( 95 % CI , 20.4 to 38.6 months ) in arm B. The hazard ratio was 1.04 ( arm A v arm B : 95 % CI , 0.66 to 1.53 ; P=.99 ) . Median survival for the PP population was 32.1 months ( 95 % CI , 22.8 to 42.2 months ) in arm A and 28.5 months ( 95 % CI , 19.5 to 38.6 months ) in arm B ( P=.49 ) . Eighty-five percent of patients in arm A and 16 % of patients in arm B experienced grade 3 or 4 toxicity . The quality of life was temporarily negatively affected in arm A. CONCLUSION The FU , cisplatin , and IFN α-2b plus radiotherapy regimen did not improve the survival compared with FU monotherapy . Given the substantial adverse effects , this treatment can currently not be recommended . Nevertheless , the outcome in both arms represents the best survival , to our knowledge , ever reported for patients with resected pancreatic cancer in r and omized controlled trials . Future studies will demonstrate whether immune response to IFN α-2b challenge has a predictive value PURPOSE We conducted a phase II trial to assess the outcomes of patients who received preoperative gemcitabine-based chemoradiation and pancreaticoduodenectomy ( PD ) for stage I/II pancreatic adenocarcinoma . PATIENTS AND METHODS Eligible patients with pancreatic head/uncinate process adenocarcinoma and radiographically defined potentially resectable disease received chemoradiation with 7 weekly intravenous ( IV ) infusions of gemcitabine ( 400 mg/m(2 ) IV over 30 minutes ) plus radiation therapy ( 30 Gy in 10 fractions over 2 weeks ) . 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 86 patients . At the time of restaging , disease progression or a decline in performance status precluded 13 patients from surgery . Seventy-three ( 85 % ) of 86 patients were taken to surgery , extrapancreatic disease was found in nine , and 64 ( 74 % ) of 86 underwent a successful PD . Median overall survival ( 86 patients ) was 22.7 months with a 27 % 5-year survival . Median survival was 34 months for the 64 patients who underwent PD and 7 months for the 22 unresected patients ( P < .001 ) . The 5-year survival for those who did and did not undergo PD was 36 % and 0 % , respectively . CONCLUSION Preoperative gemcitabine-based chemoradiation followed by restaging and evaluation for surgery separated the study population into two different subsets : patients likely to benefit from PD ( n = 64 ) and those in whom surgery would be unlikely to provide clinical benefit ( n = 22 ) . Furthermore , the encouraging overall survival observed in this large trial supports the continued investigation of gemcitabine-based preoperative therapy in resectable pancreatic cancer OBJECTIVE This study was design ed to evaluate prospect ively survival after pancreaticoduodenectomy for pancreatic adenocarcinoma , comparing two different postoperative adjuvant chemoradiation protocol to those of no adjuvant therapy . SUMMARY BACKGROUND DATA Based on limited data from the Gastrointestinal Tumor Study Group , adjuvant chemoradiation therapy has been recommended after pancreaticoduodenectomy for adenocarcinoma of the head , neck , or uncinate process of the pancrease . However , many patients continue to receive no such therapy . METHODS From October 1991 through September 1995 , all patients with resected , pathologically confirmed adenocarcinoma of the head , neck , or uncinate process of the pancreas were review ed by a multidisciplinary group ( surgery , radiation oncology , medical oncology , and pathology ) and were offered three options for postoperative treatment after pancreaticoduodenectomy : 1 ) st and ard therapy : external beam radiation therapy to the pancreatic bed ( 4000 - 4500 cGy ) given with two 3-day fluorouracil ( 5-FU ) courses and followed by weekly bolus 5-FU ( 500 mg/m2 per day ) for 4 months ; 2 ) intensive therapy : external beam radiation therapy to the pancreatic bed ( 5040 - 5760 cGy ) with prophylactic hepatic irradiation ( 2340 - 2700 cGy ) given with and followed by infusional 5-FU ( 200 mg/m2 per day ) plus leucovorin ( 5 mg/m2 per day ) for 5 of 7 days for 4 months ; or 3 ) no therapy : no postoperative radiation therapy or chemotherapy . RESULTS Pancreaticoduodenectomy was performed in 174 patients , with 1 in-hospital death ( 0.6 % ) . Ninety-nine patients elected st and ard therapy , 21 elected intensive therapy , and 53 patients declined therapy . The three groups were comparable with respect to race , gender , intraoperative blood loss , tumor differentiation , lymph node status , tumor diameter , and resection margin status . Univariate analyses indicated that tumor diameter < 3 cm , intraoperative blood loss < 700 mL , absence of intraoperative blood transfusions , and use of adjuvant chemoradiation therapy  were associated with significantly longer survival ( p < 0.05 ) . By Cox proportional hazards survival analysis , the most powerful predictors of outcome were tumor diameter , intraoperative blood loss , status of resection margins , and use of postoperative adjuvant therapy . The use of postoperative adjuvant chemoradiation therapy was a predictor of improved survival ( median survival , 19.5 months compared to 13.5 months without therapy ; p = 0.003 ) . The intensive therapy group had no survival advantage when compared to that of the st and ard therapy group ( median survival , 17.5 months vs. 21 months , p = not significant ) . CONCLUSIONS Adjuvant chemoradiation therapy significantly improves survival after pancreaticoduodenectomy for adenocarcinoma of the head , neck , or uncinate process of the pancreas . Based on these survival data , st and ard adjuvant chemoradiation therapy appears to be indicated for patients treated by pancreaticoduodenectomy for adenocarcinoma of the head , neck , or uncinate process of the pancreas .  Intensive therapy conferred no survival advantage over st and ard therapy in this analysis Two groups of patients with adenocarcinoma of the pancreas treated with either preoperative chemoradiation ( preop CTRT ) or postoperative chemoradiation ( postop CTRT )  were retrospectively analyzed for various treatment-related parameters . Between November 1986 and October 1996 , a total of 70 patients with pancreatic adenocarcinoma were enrolled into preop CTRT protocol s at our institution . Twenty-five patients with adenocarcinoma of the head of the pancreas underwent pancreaticoduodenectomy with curative intent .  After the closure of the preop CTRT protocol s , we had the opportunity to perform 23 pancreatic resections without preop CTRT . After surgery , these patients were advised to undergo CTRT . These two groups of patients were therefore selected consecutively , dependent only on the time of referral and no other bias . These two cohorts of patients are compared for various intraoperative parameters , length of hospital stay , pathologic findings , time to recurrence , and survival .  Mean age was 65 and 66 years in the preop and postop CTRT groups , respectively . Sex distribution was almost equal . Treatment breaks result ing in greater than 1 week delay in the radiotherapy occurred in 2 ( 8 % ) of 25 patients in the preop CTRT group ( myelotoxicity in 1 case and biliary sepsis in 1 case ) , whereas no treatment breaks > 1 week occurred in those receiving postop CTRT . Eleven patients in preop CTRT had grade 3 or 4 toxicity , whereas none was noted in those with postop CTRT . There was one postoperative death in the preop CTRT group and none in the postop CTRT group . Mean time to the start of CTRT was 45 days ( range , 20 - 66 days ) after pancreaticoduodenectomy . Delay of > 60 days to the onset of CTRT occurred in 2 ( 22 % ) patients and was attributable to patient delays in time to recover from surgery or patient noncompliance . Furthermore , 5 of 23 patients ( 22 % ) in the postop CTRT group did not receive treatment for various reasons . Average estimated operative blood loss was 1933 mL ( median 1550 ) and 1060 mL ( median 1000 ) for preop and postop CTRT groups , respectively . Mean length of operation was 488 minutes ( median 480 ) and 486 minutes ( median 480 ) . Median length of postoperative stay was 22 and 20 days ( ranges , 9 - 144 and 10 - 38 ) . Pathological findings in the resected specimens showed significantly fewer involved nodes in the preop CTRT group ( 28 vs 87 % ; P = 0.0006 ) , whereas similar numbers of nodes/patient were counted in each group ( 14 vs 22 , P = 0.11 ) . More negative resection margins were observed in the preop CTRT group ( 28 vs 56 % ; P = not significant ) . A significantly greater amount of fibrosis replacing the tumor was observed in the preop CTRT group ( 70 vs 40 % ; P = 0.0001 ) . There were no significant survival differences observed ( median 20 months vs 25 months ; P = 0.48 ) , in follow-up that ranged from 4 to 76 months ( median 44 months for surviving patients ) for the preop group and 4 to 40 months ( median 16 months for surviving patients ) for those with postop CTRT . Local failure either alone or as a component of distant failure occurred in 16 per cent ( 4 of 25 patients ) with preop CTRT and 16.6 per cent ( 3 of 18 ) with postop CTRT . Analysis of differences between those treated with preoperative and postoperative CTRT demonstrates similarity in toxicity and effects . However , 22 per cent of patients intended for postoperative therapy did not receive treatment 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 The Gastrointestinal Tumor Study Group ( GITSG ) previously demonstrated a significant survival advantage for patients who receive adjuvant combined radiation and chemotherapy following curative resection of pancreatic cancer.1  Median survival in the group r and omized to control was 10.9 months , compared with 21.0 months for those r and omized to treatment . GITSG registered 30 additional patients , who received the adjuvant therapy to demonstrate that the results of the r and omized trial could be replicated . Characteristics of registered patients were similar to those of patients in the r and omized phase , with the exception of an improved performance status . The registered patients had median survival time of 18 months . Ten patients were alive at 18.9 to 42.4 months ( median , 25.0 ) . Two‐year actuarial survival was 46 % ( 95 % confidence interval [ CI ] , 0.28 , 0.65 ) compared with 43 % ( 95 % CI , 0.25 , 0.63 ) for 21 patients r and omized to treatment and 18 % ( 95 % CI , 0.08 , 0.36 ) for 22 patients r and omized to control . Based on the original study and the confirmatory findings , the combined use of radiation therapy and fluorouracil as adjuvant therapy after curative resection is effective and is preferred to no adjuvant therapy PURPOSE The role of adjuvant chemoradiotherapy ( CRT ) in resectable pancreatic cancer is still debated . This r and omized phase II intergroup study explores the feasibility and tolerability of a gemcitabine-based CRT regimen after R0 resection of pancreatic head cancer . PATIENTS AND METHODS Within 8 weeks after surgery , patients were r and omly assigned to receive either four cycles of gemcitabine ( control arm ) or gemcitabine for two cycles followed by weekly gemcitabine with concurrent radiation ( 50.4 Gy ; CRT arm ) . The primary objective was to exclude a < 60 % treatment completion and a > 40 % rate of grade 4 hematologic or GI toxicity in the CRT arm with type I and II errors of 10 % . Secondary end points were late toxicity , disease-free survival ( DFS ) , and overall survival ( OS ) . RESULTS Between September 2004 and January 2007 , 90 patients were r and omly assigned ( 45:45 ) . Patient characteristics were similar in both arms . Treatment was completed per protocol by 86.7 % and 73.3 % ( 80 % CI , 63.1 % to 81.9 % ; 95 % CI , 58.1 % to 85.4 % ) in the control and CRT arms , respectively , and grade 4 toxicity was 0 % and 4.7 % ( two of 43 ; 80 % CI , 1.2 % to 11.9 % ) , respectively . In the CRT arm , three patients experienced grade 3-related late toxicity . Median DFS was 12 months in the CRT arm and 11 months in the control arm . Median OS was 24 months in both arms . First local recurrence was less frequent in the CRT arm ( 11 % v 24 % ) . CONCLUSION Adjuvant gemcitabine-based CRT is feasible , well-tolerated , and not deleterious ; adding this treatment to full-dose adjuvant gemcitabine after resection of pancreatic cancer should be evaluated in a phase III trial In locally advanced pancreatic cancer , the utilization of chemotherapy and radiotherapy is increasing , although in view of the reported long-term results of several contemporary trials , further improvements are certainly needed . Encouraging results using the combination of cisplatin , cytarabine , caffeine , and continuous infusion ( CI ) 5-fluorouracil ( 5-FU ) ( PACE ) for the treatment of advanced pancreatic carcinoma prompted a phase II study using PACE followed by external beam radiotherapy with CI of 5-FU ( PACE-RT ) for localized disease . Forty-one patients were treated with PACE-RT as adjuvant therapy after surgical resection ( 21 patients ) , or as primary therapy for locally advanced , unresectable disease ( 20 patients ) , with reevaluation for resection after completion of treatment . PACE consisted of cisplatin 100 mg/m2 IV on day 1 , cytarabine 2 g/m2 IV every 12 hours × 2 doses , and caffeine 400 mg/m2 subcutaneously after each cytarabine dose ; and days 3 to 21 , 5-FU 250 mg/m2/d given by CI . Cycles were repeated every 28 days . After 2 cycles of PACE , radiation therapy was given concurrently with 5-FU at 200 mg/m2/d . In the adjuvant setting , the tumor bed and the draining lymph node basin received 50.4 Gy and 45 Gy , respectively . In the neoadjuvant setting , the primary and regional lymph nodes were to receive 39.6 Gy followed by a neutron boost of 8 NGy to the gross tumor volume . Photon therapy was delivered at 1.8 Gy per fraction and neutron therapy at 0.8 NGy per fraction , 5 days a week . All patients were evaluable for toxicity and survival . The most common toxicity was myelosuppression , with grade III to IV neutropenia occurring in 59 % of the patients . The median survival times in the locally advanced and adjuvant patients were 13.4 and 18.1 months , with 1-year survival rates of 52 % and 65 % , respectively . Nine of 20 patients receiving PACE-RT for unresectable carcinoma had sufficient tumor regression to meet clinical criteria for exploration ; three were resected with curative intent . The survival of these three patients undergoing resection after neo-adjuvant therapy was 22.4 , 24.3 and 40 months . The treatment program was active , but only moderately well tolerated . Modification of this regimen with newer , less toxic drugs may provide better results and reduced toxicity 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 AIMS To evaluate a single centre 's experience with pancreatic carcinoma focused on preoperative chemoradiation therapy ( CRT ) for treatment of locally advanced pancreatic carcinoma . The aim of the present analysis was to evaluate the median overall survival time ( OS ) after preoperative CRT and to compare it with OS after primary resection of pancreatic carcinoma . In conclusion a new treatment strategy was developed using multimodality treatment for pancreatic carcinoma deemed to be resectable by CT-scan . PATIENTS AND METHODS Between 1995 and 2003 , 302 patients with ductal adenocarcinoma of the pancreatic head and body were recorded prospect ively and OS was analysed with regard to therapy . RESULTS Fifty-eight patients were resected without any pretreatment and had an OS of 21 months . Twenty-one patients with initially unresectable tumours underwent CRT followed by resection and had an OS of 54 months , which was not significantly different from primary resection ( p=0.315 ) . Lymph node metastasis was significantly reduced after CRT ( p=0.0029 ) . OS for patients whose tumours could not be resected was 3 - 10 months , depending on tumour stage and consecutive therapy . CONCLUSION CRT pretreatment was effective in locally advanced pancreatic carcinoma and result ed in resection of tumours otherwise staged as non-resectable . This experience led to a r and omized trial for patients who by CT are staged to have resectable cancer of the pancreatic head with the intent to increase curative resectability and survival by neoadjuvant CRT ( IS RCT N78805636/NCT00335543 ) 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 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 Resection of pancreatic carcinoma is re source ‐intensive with a limited impact on survival . Chemotherapy and /or radiotherapy ( RT ) have been shown to be effective palliation . To examine whether preoperative chemoradiotherapy as the initial treatment improves survival for patients with a regional pancreatic adenocarcinoma with a minimal chance of being resected successfully , an outcomes trial was conducted Background : Success of surgical treatment for pancreatic and periampullary cancer is often limited due to locoregional recurrence and /or the development of distant metastases . Objective : The survival benefit of celiac axis infusion ( CAI ) and radiotherapy ( RT ) versus observation after resection of pancreatic or periampullary cancer was investigated . Methods : In a r and omized controlled trial , 120 consecutive patients with histopathologically proven pancreatic or periampullary cancer received either adjuvant treatment consisting of intra-arterial mitoxantrone , 5-FU , leucovorin , and cisplatinum in combination with 30 × 1.8 Gy radiotherapy ( group A ) or no adjuvant treatment ( group B ) . Groups were stratified for tumor type ( pancreatic vs. periampullary tumors ) . Results : After surgery , 120 patients were r and omized ( 59 patients in the treatment group , 61 in the observation group ) . The median follow-up was 17 months . No significant overall survival benefit was seen ( median , 19 vs. 18 months resp . ) . Progressive disease was seen in 86 patients : in 37 patients in the CAI/RT group , and in 49 patients in the observation group ( log-rank P < 0.02 ) . Subgroup analysis showed significantly less liver metastases after adjuvant treatment in periampullary tumors ( log-rank P < 0.03 ) without effect on local recurrence . Nonetheless , there was no significant effect on overall survival in these patients ( log-rank P = 0.15 ) . In patients with pancreatic cancer  , CAI/RT had no significant effect on local recurrence ( log-rank P = 0.12 ) neither on the development of liver metastases ( log-rank P = 0.76 ) and consequently , no effect on overall survival . Conclusion : This adjuvant treatment schedule results in a prolonged time to progression . For periampullary tumors , CAI/RT induced a significant reduction in the development of liver metastases , with a possible effect on overall survival . Especially in these tumors , CAI/RT might prove beneficial in larger groups and further research is warranted Purpose Although the outcome of surgery for locally advanced pancreatic cancer remains poor , it is improving , with 5-year survival up to about 10 % in Japan . The preliminary results of our multi-institutional r and omized controlled trial revealed better survival after surgery than after radiochemotherapy . We report the final results of this study after 5 years of follow-up . Methods Patients with preoperative findings of pancreatic cancer invading the pancreatic capsule without involvement of the superior mesenteric or common hepatic arteries , or distant metastasis , were included in this r and omized controlled trial , with their consent . If the laparotomy findings were consistent with these criteria , the patient was r and omized to a surgery group or a radiochemotherapy group ( 5-fluorouracil 200 mg/m2/day and 5040 Gy radiotherapy ) . We compared the mean survival time , 3- and 5-year survival rates , and hazard ratio . Results The  surgery and radiochemotherapy groups comprised 20 and 22 patients , respectively . Patients were followed up for 5 years or longer , or until an event occurred to preclude this . The surgery group had significantly better survival than the radiochemotherapy group ( P < 0.03 ) . Surgery increased the survival time and 3-year survival rate by an average of 11.8 months and 20 % , respectively , and it halved the instantaneous mortality ( hazard ) rate . Conclusion Locally invasive pancreatic cancer without distant metastases or major arterial invasion is treated most effectively by surgical resection
Abstract Objective Controversy remains existed whether chemoradiotherapy ( CRT ) , especially neoadjuvant chemoradiotherapy ( neoadjuvant CRT ) achieves a significant benefit in resectable pancreatic cancer ( PC ) treatment .
In this meta- analysis , we aim ed to clarify the benefits of CRT and neoadjuvant CRT in resectable PC .