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. Pancreaticoduodenectomy for pancreatic adenocarcinoma: postoperative adjuvant chemoradiation improves survival. A prospective, single-institution experience. Resected adenocarcinoma of the pancreas— 616 patients: Results, outcomes, and prognostic indicators Postoperative adjuvant gemcitabine and concurrent radiation after curative resection of pancreatic head carcinoma: a phase II study. Regional Targeting Chemoimmunotherapy in Patients Undergoing Pancreatic Resection in an Advanced Stage of Their Disease: A Prospective Randomized Study A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. Interferon-based adjuvant chemoradiation therapy improves survival after pancreaticoduodenectomy for pancreatic adenocarcinoma. Treatment of Pancreatic Cancer: Challenge of the Facts A phase I study of radiation therapy and twice-weekly gemcitabine and cisplatin in patients with locally advanced pancreatic cancer.
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 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 This large-volume , single-institution review examines factors influencing long-term survival after resection in patients with adenocarcinoma of the head , neck , uncinate process , body , or tail of the pancreas . Between January 1984 and July 1999 inclusive , 616 patients with adenocarcinoma of the pancreas underwent surgical resection .  A retrospective analysis of a prospect ively collected data base was performed . Both univariate and multivariate models were used to determine the factors influencing survival . Of the 616 patients , 526 ( 85 % ) underwent pancreaticoduodenectomy for adenocarcinoma of the head , neck , or uncinate process of the pancreas , 52 ( 9 % ) underwent distal pancreatectomy  for adenocarcinoma of the body or tail , and 38 ( 6 % ) underwent total pancreatectomy for adenocarcinoma extensively involving the gl and . The mean age of the patients was 64.3 years , with 54 % being male and 91 % being white . The overall perioperative mortality rate was 2.3 % , whereas the incidence of postoperative complications was 30 % . The median postoperative length of stay was 11 days . The mean tumor diameter was 3.2 cm , with 72 % of patients having positive lymph nodes , 30 % having positive resection margins , and 36 % having poorly differentiated tumors . Patients undergoing distal pancreatectomy for left-sided lesions had larger tumors ( 4.7 vs. 3.1 cm , P < 0.0001 ) , but fewer node-positive resections ( 59 % vs. 73 % , P = 0.03 ) and fewer poorly differentiated tumors ( 29 % vs. 36 % , P<0.001 ) , as compared to those undergoing pancreaticoduodenectomy for right-sided lesions . The overall survival of the entire cohort was 63 % at 1 year and 17 % at 5 years , with a median survival of 17 months . For right-sided lesions the 1- and 5-year survival rates were 64 % and 17 % , respectively , compared to 50 % and 15 % for left-sided lesions . Factors shown to have favorable independent prognostic significance by multivariate analysis were negative resection margins ( hazard ratio [ HR ] = 0.64 , confidence interval [ CI ] = 0.50 to 0.82 , P = 0.0004 ) , tumor diameter less than 3 cm ( HR = 0.72 , CI = 0.57 to 0.90 , P = 0.004 ) , estimated blood loss less than 750 ml ( HR = 0.75 , CI = 0.58 to 0.96 , P = 0.02 ) , well/moderate tumor differentiation ( HR = 0.71 , CI = 0.56 to 0.90 , P = 0.005 ) , and postoperative chemoradiation ( HR = 0.50 , CI = 0.39 to 0.64 , P } < 0.0001 ) . Tumor location in head , neck , or uncinate process approached significance in the final multivariate model ( HR = 0.60 , CI = 0.35 to 1.0 , P = 0.06 ) . Pancreatic resection remains the only hope for long-term survival in patients with adenocarcinoma of the pancreas . Completeness of resection and tumor characteristics including tumor size and degree of differentiation are important independent prognostic indicators . Adjuvant chemoradiation is a strong predictor of outcome and likely decreases the independent significance of tumor location and nodal status PURPOSE The addition of radiation to adjuvant 5-fluorouracil for the treatment of pancreatic cancer has not yet shown any definite benefit . Gemcitabine ( GEM ) has potential activity in advanced pancreatic cancer and is a powerful radiosensitizer . We evaluated the feasibility of postoperative administration of GEM alone , followed by concurrent GEM and irradiation ( RT ) after curative resection for pancreatic adenocarcinoma . METHODS AND MATERIAL S GEM 1000 mg/m(2 ) on Days 1 and 8 every 21 days for three courses was given within 8 weeks after surgery and was followed by GEM 300 mg/m(2 ) weekly + 40 Gy in a split course . Twenty-two patients ( median age 59 years , range 39 - 74 , Performance Status 0 - 1 ) with Stage II and III curatively resected pancreatic head adenocarcinoma were included . RESULTS For GEM alone , all patients received the three planned courses , with dose reductions in 7 ( 32 % ) of 22 patients . All patients , except two , completed full chemoradiation ; one received only 20 Gy because of both World Health Organization Grade 4 vomiting and thrombopenia and the other stopped RT after 32 Gy because of early disease progression . No reduction in GEM during RT was necessary ; no toxic death was noted ; and World Health Organization Grade 3 - 4 hematologic and nonhematologic toxicities occurred in 8 ( 36 % ) and 7 ( nausea , vomiting ) ( 32 % ) of 22 patients respectively . No late toxicity developed . After a median follow-up of 15 months , 11 patients were alive , and 2 patients had died of causes unrelated to their disease or toxicity , The median disease-free survival and overall survival was 6 and 15 months , respectively . CONCLUSION This adjuvant regimen was well tolerated and can be easily administered after curative surgery for pancreatic cancer . Its intensification with continuous RT is currently being investigated Purpose To evaluate in a prospect i ve r and omized study the long-term results of adjuvant locoregional chemoimmunotherapy in a number of patients with stage III pancreatic duct cancer who underwent pancreatic resection between November 1993 and October 2000 . Methods One hundred twenty-eight patients were divided into three groups . Group A ( n = 40 ) patients had surgical resection alone . Group B ( n = 45 ) patients had , using a side arterial branch of the jejunal artery , an arterial catheter advanced under fluoroscopic control into the superior mesenteric artery . Group B patients also received adjuvant chemotherapy . Group C ( n = 43 ) patients had the same kind of arterial catheter and received as an adjuvant treatment locoregional chemoimmunotherapy . During the initial surgical exploration , all patients underwent pancreatic resection . Pancreatic resection involved a st and ard technique of extended duodenopancreatectomy with regional lymphadenectomy and was carried out in all patients by the first author . At the end of intervention , all patients were r and omly assigned to the above-mentioned groups . R and omization was based mainly on histologic evidence of the stage of the disease . Results The 2- and 5-year survival rates were 29 % and 0 % for group A , 52 % and 10 % for group B , and 65 % and 18 % for group C. The respective percentages for disease-free survival were 20 % and 0 % for group A , 35 % and 7 % for group B , and 58 % and 11 % for group C. Since statistical differences among groups were observed from the second and third years , the study was interrupted early for ethical reasons . Conclusions When applied regionally , combined chemoimmunotherapy is simple , safe , and effective . This type of therapy offers substantial advantages in terms of prolonging overall survival and improving disease-free survival compared to surgical resection alone or to surgical resection and adjuvant regional chemotherapy 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 BACKGROUND Based on a 2-year survival of 43 % , the Gastrointestinal Tumor Study Group ( GITSG ) recommended adjuvant 5-FU-based chemoradiation for resected patients with adenocarcinoma of the pancreatic head . Here we report improved survival over the GITSG protocol with a novel adjuvant chemoradiotherapy based on interferon-alpha ( IFNalpha ) . METHODS From July 1993 to September 1998 , 33 patients with adenocarcinoma of the pancreatic head underwent pancreaticoduodenectomy ( PD )  and subsequently went on to adjuvant therapy ( GITSG-type , n = 16 ) or IFNalpha-based ( n = 17 ) typically given between 6 and 8 weeks after surgery . The latter protocol consisted of external-beam irradiation at a dose of 4,500 to 5,400 cGy ( 25 fractions per 5 weeks ) and simultaneous three-drug chemotherapy consisting of ( 1 ) continuous infusion 5-FU ( 200 mg/m2 per day ) ; ( 2 ) weekly intravenous bolus cisplatin ( 30 mg/m2 per day ) ; and ( 3 ) IFNalpha ( 3 million units subcutaneously every other day ) during the 5 weeks of radiation . This was then followed by two 6-week courses of continuous infusion 5-FU ( 200 mg/m2 per day , given weeks 9 to 14 and 17 to 22 ) . Risk factors for recurrence and survival were compared for the two groups . RESULTS A more advanced tumor stage was observed in the IFNalpha-treated patients ( positive nodes and American Joint Committee on Cancer [ AJCC ] stage III = 76 % ) than the GITSG group ( positive nodes and stage III = 44 % , P = 0.052 ) . The 2-year overall survival was superior in the IFNalpha cohort ( 84 % ) versus the GITSG group ( 54 % ) . With a mean follow-up of 26 months in both cohorts , actuarial survival curves significantly favored the IFNalpha group ( P = 0.04 ) . CONCLUSIONS With a limited number of patients , this phase II type trial suggests better survival in the interferon group as compared with the GITSG group even though the interferon group was associated with a more extensive tumor stage . The 2-year survival rate in the interferon group is the best published to date for resected pancreatic cancer . The interferon/cisplatin/5-FU-based adjuvant chemoradiation protocol appears to be a promising treatment for patients who have undergone PD for adenocarcinoma of the pancreatic head Adenocarcinoma of the pancreas is associated with the worst survival of any form of gastrointestinal malignancy . In spite of the progress in surgical treatment , result ing in increasing resection rates and a decrease in treatment-related morbidity and mortality , the true figures of cure are even today below 3 % . The dissemination of pancreatic cancer behind the local tissue compartments restricts the short-term ( < 3 years ) and long-term outcome for patients who have undergone resection . By histological evaluation , less than 15 % of the patients undergoing R0 resection have a pN0 status , more than 60 % suffer from lymph angiosis carcinomatosa , and more than 50 % suffer extrapancreatic nerve plexus infiltration . Hematoxylin and eosin – negative lymph nodes were found to be cancer positive when reverse transcriptase polymerase chain reaction ( RT- PCR ) or immunostaining was applied to the HE-negative lymph nodes . Cancer of the uncinate process has a very poor prognosis because there are no early symptoms ; vessel wall involvement occurs early and frequently ; a high association of liver metastasis exists as well . Surgery offers a low success rate , but it provides the only chance of cure . Ductal pancreatic cancer is diagnosed in more than 95 % of the cases in an advanced stage ; potentially curative resection can be performed only in about 10%–15 % of these patients . Major contributions of surgery to improved treatment results are the reduction of surgical morbidity — e.g . , early postoperative local and systemic complications— and a decrease of hospital mortality below 3%–5 % . In most recently published prospect i ve trials , R0 resection has been reported to result in an increase in short-term survival beyond that recorded for patients with residual tumor . However , R0 resection fails to improve long-term survival . In many published R0 series , st and ard tissue resection of pancreatic head cancer with the Kausch-Whipple procedure failed to include remote cancer cell – positive tissues in the operative specimen ; e.g. , N2-lymph nodes , nerve plexus , and perivascular extrapancreatic and retropancreatic tissues were not excised . Cancer recurrence after so-called R0 resection with curative intent is frequently the consequence of cancer left behind . Thus , long-term survival ( > 5 years ) is observed in a very small group of patients , contradicting the published 5-year actuarial survival rates of 20%–45 % for resected patients . The assessment of clinical benefit from surgical or medical cancer treatment should therefore be based on several end points , not only on actuarial survival . Publication of actuarial survival figures must include the number of observed ( actual ) survivals , the definition of the subset of patients followed after resection , and the total number of patients in the study group ; anything less is misleading . In reporting pancreatic cancer treatment trial results after oncological resections , more convincing primary end points to evaluate treatment efficacy are median survival ( in months ) , actual survival at 1–5 years , and progression-free survival ( in months ) . In series with multimodality treatment , clinical benefit response as well as quality of life measurements using the EORTC Quality of Life index C30 ( QLQ-C30 ) are of importance in evaluating survival data . Adjuvant treatment improves survival after oncological resection ; however , the short-term and long-term benefit after adjuvant chemotherapy in R0 as well as in R1 - 2 resected patients has not yet been underscored by data from controlled clinical trials . The survival benefit ( median survival time ) of adjuvant chemotherapy or radiochemotherapy has been demonstrated to be 6–10 months . Therefore , after oncological resection of pancreatic cancer each patient should be offered adjuvant treatment . A neoadjuvant treatment protocol for pancreatic cancer , however , has not been established PURPOSE In vitro studies suggest that low-dose gemcitabine sensitizes cells to radiation therapy and that this effect persists for 48 h after drug exposure . Cisplatin is a radiation sensitizer and is also synergistic with gemcitabine in some in vitro tumor systems . Gemcitabine 's radiosensitizing properties can theoretically be exploited by twice-weekly administration . This study assessed toxicity in patients with pancreatic cancer treated with radiation therapy , gemcitabine , and cisplatin .  METHODS AND MATERIAL S Patients with locally advanced pancreatic or gastric cancer were eligible .  Gemcitabine and cisplatin were given twice weekly for 3 weeks during radiation therapy ( 50.4 Gy in 28 fractions ) . The starting dose of gemcitabine was 5 mg/m(2 ) i.v . The starting dose for cisplatin was 5 mg/m(2 ) . Chemotherapy doses escalated every 3 to 6 patients according to a st and ard Phase I study design . RESULTS Twenty-four evaluable patients , all with pancreatic cancer , were treated on this protocol . Grade 3 neutropenia occurred in 2 patients , Grade 3 thrombocytopenia occurred in 2 , and Grade 4 lymphopenia occurred in 1 . There was no clear relationship between chemotherapy dose and hematologic toxicity . The most common Grade 3 - 4 nonhematologic toxic responses were vomiting ( 7 patients ) and nausea ( 7 patients ) . Dose-limiting toxicity consisting of Grade 4 nausea and vomiting occurred in 2 of 3 patients at dose Level 6 ( gemcitabine 45 mg/m(2 ) i.v . and cisplatin 10 mg/m(2 ) i.v . ) . Six patients were treated at dose Level 5 ( gemcitabine 30 mg/m(2 ) i.v . and cisplatin 10 mg/m(2 ) i.v . ) without dose-limiting toxicity . CONCLUSION Gemcitabine 30 mg/m(2 ) i.v . twice weekly and cisplatin 10 mg/m(2 ) i.v . twice weekly may be given concurrently with radiation therapy ( 50.4 Gy in 28 fractions ) with acceptable toxicity
The objective of this study was to determine the effect , if any , on survival of adjuvant 5-FU-based chemoradiotherapy following pancreaticoduodenectomy for pancreatic carcinoma .