Adjuvant therapy in pancreatic cancer

 Paula Ghaneh, John Slavin, Robert Sutton, Mark Hartley, John P Neoptolemos

Department of Surgery, University of Liverpool, 5th Floor UCD Building, Daulby Street, Liverpool, L69 3GA, UKª¤
Correspondence to  Professor JP Neoptolemos, Department of Surgery, University of Liverpool,  5th Floor UCD Building,
Daulby Street, Liverpool,  L69 3GA, UK. j.p.neoptolemos@liverpool.ac.uk
Tel: 0044-151-706-4175, Fax: 0044-151-706-5798ª¤
Received 2001-05-15 Accepted 2001-06-15


Abstract 

The outlook for patients with pancreatic cancer has been grim. There have been major advances in the surgical treatment of pancreatic cancer, leading to a dramatic reduction in postª²operative mortality from the development of high volume specialized centres. This stimulated the study of adjuvant and neoadjuvant treatments in pancreatic cancer including chemoradiotherapy and chemotherapy. Initial protocols have been based on the original but rather small GITSG study first reported in 1985. There have been two large European trials totalling over 600 patients (EORTC and ESPAC-1) that do not support the use of chemoradiation as adjuvant therapy. A second major finding from the ESPAC-1 trial (541 patients randomized) was some but not conclusive evidence for a survival benefit associated with chemotherapy. A third major finding from the ESPAC-1 trial was that the quality of life was not affected by the use of adjuvant treatments compared to surgery alone. The ESPAC-3 trial aims to assess the definitive use of adjuvant chemotherapy in a randomized controlled trial of 990 patients.

Subject headings  pancreatic neoplasms/drug therapy; pancreatic neoplasms/radiotherapy; human; review

Ghaneh P, Slavin J, Sutton R, Hartley M, Neoptolemos JP. Adjuvant therapy in pancreatic cancer.
World J Gastroenterol, 2001;7(4):482-489



INTRODUCTIONª¤

Pancreatic cancer is the 5th most common site of deaths due to cancer among all cancer sites in the Western world. Low cure rates ensure that the mortality is nearly as high as the incidence. It is responsible for 7000 deaths per year in the UK^£Û1£Ý, ª©40000 per year in Europe and 28000 in the USA^£Û2£Ý. The peak mortality ages are estimated to be between 65 and 72 years in Europe and 55 and 75 years in the USA^£Û2£Ý. The incidence of this deadly disease has been rising during the last century. In the past 20 years however, there have been vast improvements in the surgical management of patients with pancreatic cancer. The surgical procedures have been improved and become more standardized between centres and countries. The level of pre- and post-operative support for these patients has been optimized, particularly in established centres with a high throughput^£Û3£Ý. These measures have ensured that the outlook for patients with resectable disease has certainly improved, particularly in the short term. Extending patient survival still remains a problem. The overall five-year survival for all patents with pancreatic cancer is only 0.4%^£Û4£Ý. Patients who are suitable for resection have five-year survival rates of between 10% and 24%^£Û5-8£Ý and are virtually never cured. Therefore, even for the 10% to 15% of patients who undergo surgery, there appears to be no guarantee of cure or indeed long- term survival. These outcomes would suggest a role for the use of additional or adjuvant therapy to attempt to improve patient survival and quality of life.ª¤ª¤

RADICAL SURGERYª¤

Japanese groups amongst others have been enthusiastic in pursuing radical resection as means of increasing disease free margins and thus hopefully improving patient survival. Radical surgery includes extensive lymph node dissection and retroperitoneal connective tissue clearance as well as pancreatic resection. The Japanese groups have suggested that these approaches are superior to conventional Kausch-Whipple resection but several studies have not shown significant survival advantages when compared with conventional
resection^£Û9-13£Ý. Kayahara et alª« found that radical resection in patients with Stage ¢ñ and ¢ò disease (Japanese classification) and clear margins (R0) resulted in a reduction of local recurrence but did not translate into improved survival because of hepatic
metastases^£Û14£Ý. Interestingly highly detailed serial section analysis of presumed R0 specimens has revealed microscopic margin disease (R1) in up to 38% of specimens^£Û14£Ý.ª¥ 
           Difficulties are encountered when comparing survival figures of Western and Japanese studies because of the different staging systems used (UICC vs JPS respectively). This is because of the phenomenon of ¡®staging system migration¡¯ that may give apparently better survival for each stage in one system compared to the other even though there is no overall difference in survival. Satake et al^{ª«£Û15£Ý} compared the Japanese and UICC staging systems in a large cohort of patients. Stage for stage the Japanese system revealed a better survival from Stage ¢ñ to ¢ô compared with UICC system. The overall five-year survival however, was the same (11%) because the systems had been analysed in identical patients.ª¥
           The majority of radical resection studies have been non-randomized and performed in single institutions. The radical lymph node dissection allows more accurate staging of disease and these tumours will tend to be upstaged because of this. Thus it is necessary to examine overall group survival within the context of randomized studies by an intention to treat analysis. There has been one multicentre prospective randomized trial comparing traditional partial pancreatoduodenectomy with and without a more extensive lymph node dissection^£Û16£Ý. Eighty-one patients were randomized to receive a standard (n=40) or extended (n=41) lymphadenectomy and retroperitoneal soft tissue clearance.
          The standard lymphadenectomy included removal of lymph nodes situated at the anterior and posterior pancreatoduodenal, pyloric, main bile duct, superior and inferior pancreatic head and pancreatic body stations. The extended lymphadenectomy also included the removal of lymph nodes from the hepatic hilum, along the aorta from the diaphragmatic hiatus to the inferior mesenteric artery, laterally to both renal hila and clearance of the coeliac trunk and superior mesenteric artery. There was no significant difference of overall survival between the two groups. Patients who had lymph node positive disease demonstrated better survival following an extended resection compared to those who did not have an extended lymphadenectomy but must be regarded as a statistically invalid manoeuvre as this was a postª²hoc subgroup analysis. In light of these findings the ultimate benefit of extended lymphadenectomy surgery still needs to be proven with further critical evaluation.ª¥
          There appears to be no additional survival benefit associated with total pancreatectomy compared to Kausch-Whipple pancreatoduodenectomy and at the present time the pylorus preserving pancreatoduodenectomy has been shown to produce similar results to the more traditional Kausch Whipple procedure^{£Û17,18£Ý}. The latter approach is now the procedure of choice in most centres.ª¥
          The lack of survival benefit associated with radical resection may be due in part to the pattern of disease recurrence in resected pancreatic cancer. Most tumour recurrences are local, peritoneal and hepatic^{£Û19-24£Ý}. The early appearance of hepatic metastases following resection almost certainly indicates the presence of hepatic micrometastases at the time of surgery. Microscopic peritoneal disease also tends to occur early in contrast to the relatively later presentation of local recurrence. Pancreatic cancer cells tend to spread within a range of peripancreatic tissues. Lymphatic infiltration and perineural invasion may be found in 90%-100% of resected
specimens^£Û25£Ý. Reasons for recurrence following an apparently curative resection include residual retroperitoneal disease, perineural invasion, hepatic micrometastases and lymph node involvement. The pattern of relapse after surgery reflects the natural course of the disease without resection. The most commonly affected organs include abdominal lymph nodes (72%-83%), liver (64%-80%), peritoneum (40%-53%) and lung (27%-50%)^£Û14£Ý. An R0 resection in patients with no lymph node metastases cannot be achieved in more than about half of the patients undergoing resection. Kayahara et al^£Û14£Ý at post mortem examined 15 patients who had undergone radical resection. The local recurrence rate in this group of patients was 80%. The local recurrences were associated with perineural invasion, lymphatic invasion and soft tissue infiltration. High rates of local recurrence have been confirmed in numerous studies of patients who have undergone pancreatoduodenectomy and the majority occur within 1 to 2 years of surgery^{£Û23,24£Ý}.
       Identification of extrapancreatic disease at the preª²operative stage has improved due to accurate imaging techniques^£Û26£Ýand laparoscopy^£Û27£Ý. Peritoneal cytology has been shown to be positive in 58% of patients who may have unresectable tumours or have a limited postoperative survival^£Û27£Ý. The best predictors of outcome following surgery also reflect the causes of disease relapse. These include tumour stage (which also includes the lymph node status), grade of primary tumour and resection margin status^{£Û28-32£Ý}. Not surprisingly patients with stage ¢ñ or ¢ò disease and negative resection margins tend to demonstrate the best survival.ª¥
          The poor overall survival of patients with pancreatic cancer, even following optimal surgical intervention, and the pattern of disease progression and recurrence are clear indications for the use of additional treatment modalities.ª¤ª¤

CHEMOTHERAPYª¤

Advanced pancreatic cancerª¤
There have been many studies of chemotherapy in patients with advanced pancreatic cancer. Single agents and combination regimens have been used. At the present time there is no accepted standard chemotherapeutic agent for the treatment of pancreatic cancer. 5-fluorouracil (5-FU) remains the most effective and most frequently used single chemotherapy agent. 5-FU works partly by interference with enzymes such as thymidylate synthase and partly by incorporation of 5-FU metabolites into DNA and RNA. The response rates of ¡«15% with a median survival of 3-5 months^£Û33£Ý. The addition of the modulator folinic acid has produced marginal survival benefit over
5-FU alone but this has not been a significant increase^£Û33£Ý. The addition of other modulators such as phosphonacetyl-L-aspartate (PALA), and interferon has also not produced significant improvements in survival^{£Û34,35£Ý}. Comparisons of 5-FU alone and 5-FU with a combination of other agents have not shown any advantage for the combination groups in randomized trials^£Û33£Ý.ª¥
          A new agent, gemcitabine has been compared to 5-FU in a randomized multi-centre phase ¢ó clinical trial^£Û36£Ý. Gemcitabine is a deoxycytidine analogue that is phosphorylated to an active form and competes with dCTP for incorporation into DNA. The study, in which over 70% of patients had stage ¢ô disease, randomized 63 patients to receive gemcitabine and 63 patients to receive 5-FU. Median survival in the gemcitabine group was 5.7 months compared to 4.4 months in the 5-FU group but no patient survived beyond 19 months. The clinical benefit response was also significantly higher in the gemcitabine group^£Û36£Ý. Despite the fact that this is the only trial with a straight comparison between the two agents gemcitabine has been recommended as the drug of choice in the USA. Gemcitabine has also been combined with 5-FU in several phase ¢ò studies. It is generally well tolerated but can have unpredictable side effects such as neutropaenia, abnormal liver function tests and nausea and vomiting. In patients who have had previous radiotherapy to the mediastinum there have been unpredictable reactions^£Û37£Ý.ª¥
          There is good evidence from several randomized controlled trials comparing chemotherapy with a no treatment group that chemotherapy is of benefit in patients with advanced pancreatic cancer. Mallinson et al^£Û38£Ý demonstrated a median survival of 11 months for patients treated with 5-FU, cyclophosphamide, methotrexate, vincristine and mitomycin C compared to 2.2 months for the untreated control group. This regimen did not produce a significantly greater survival when compared to 5-FU alone in a much larger randomized control trial^£Û39£Ý. Another rather poorly controlled study compared 5-FU and carmustine to untreated controls^£Û40£Ý. There was no significant survival benefit associated with this regimen but the majority of patients in this study received only a single treatment and did not finish the course. A further trial of the combination of 5-FU, doxorubicin and mitomycin C (FAM) resulted in median survival of 33 weeks compared with median survival of 15 weeks in untreated control patients^£Û41£Ý. A recent study compared the use of 5-FU + folinic acid (+/- etoposide) with best supportive care and showed that the median survival in the treated group was 6 months compared to 2.5 months in the control group^£Û42£Ý. Moreover there was better overall quality of life score for the treated patients.ª¤ª¤


Adjuvant chemotherapyª¤
There have been only a few studies of adjuvant chemotherapy in pancreatic cancer and (up until the ESPAC-1 trial) there was only one randomized controlled trial comparing surgery and chemotherapy with surgery alone (Table 1)^{£Û43-46£Ý}. Splinter et al^{ª«£Û43£Ý}reported no evidence of improvement or survival using a FAM regimen in 16 patients who had undergone pancreatoduodenectomy with a three year survival of 24% compared to a three year survival of 28% in 36 patients who had undergone surgery only. Patients from different time periods were included in the two groups and there were only nine patients with pancreatic ductal adenocarcinoma in the adjuvant group and 18 in the surgery only group.
           Baumel et al^£Û46£Ý reported adjuvant chemotherapy in 43 selected patients with a median survival of 12 months but there was no difference in median survival from those patients who underwent surgery only (12 months). Bakkevold et al^£Û45£Ý randomized 61 patients who had undergone pancreatoduodenectomy for pancreatic cancer or ampullary cancer to receive either six courses of FAM or no chemotherapy. There was a significant difference in the median survival rates between the two groups: 23 months. Unfortunately this did not translate into a significantly improved long-term survival however: the 5-year survival rates were 4% for the treatment arm versus 8% for the surgery only arm. There was also considerable toxicity encountered with the FAM regimen. Only 24 out of 30 patients randomized to treatment actually started therapy. Sixteen patients needed hospitalization after the first chemotherapy course and a total of 13 patients managed to complete all six cycles of FAM.ª¥
           The European Study Group for Pancreatic Cancer (ESPAC) has commenced the ESPAC-3 trial with the objective of definitively defining the role of adjuvant chemotherapy following curative resection for pancreatic ductal adenocarcinoma. Two adjuvant regimens are being studied against a no chemotherapy control: ¢Ù 5-FU + folinic acid for 24 weeks versus ¢Ú gemcitabine for 24 weeks versus ¢Û observation. All patients will have undergone potentially curative resection for pancreatic ductal adenocarcinoma. A total of 990 patients (330 in each arm) will be recruited over the next few years and survival analysis will be completed after two years of follow-up. At the present time recruitment is underway from centres across Europe with further centres in Canada, Australia and New Zealand due to join.

RADIOTHERAPY (CHEMORADIOTHERAPY)ª¤

Advanced pancreatic cancerª¤
External beam radiotherapy (EBRT) although used in the treatment of advanced pancreatic cancer, has never been compared with an untreated control arm in any randomized controlled trial. The most commonly used and probably the best radiosensitizer used with EBRT for advanced pancreatic cancer is 5-FU. Many retrospective studies of EBRT, usually in relatively small groups of selected patients report median survival times of 10-15 months with good palliation of symptoms^{£Û47,48£Ý}.ª¥
          The improved local control of disease achieved with EBRT has not translated into significantly longer survival times, so there have been various refinements in an attempt to enhance the effectiveness of radiotherapy. Wide field irradiation has been used to address the problem of hepatic micrometastases. A Radiation Therapy Oncology Group (RTOG) study of 79 patients who received pancreatic and hepatic irradiation resulted in a median survival of 8.4 months but at the expense of considerable toxicity^£Û49£Ý. Intraoperative radiation therapy (IORT) aims to deliver higher doses of radiation with greater precision and thus reducing the exposure of neighbouring organs. Experimentally, its effectiveness may be as high as five times the equivalent dose given by EBRT. In advanced pancreatic cancer the survival times achieved using IORT have not been encouraging (median survival ¡«6 months) and it has been mainly used to boost
EBRT^{£Û50,51£Ý}. A study comparing EBRT + IORT + 5-FU with EBRT +5-FU demonstrated no significant survival difference (12 and 13 months respectively)^{£Û50,51£Ý}.
          Complications encountered during IORT include, duodenal and gastric ulceration, vascular sclerosis and pancreatic abscess^£Û52£Ý. IORT offers good local control and pain relief but cannot be recommended as a standard treatment as it has not been possible to demonstrate any advantages over conventional therapy.

Adjuvant radiotherapy (chemoradiotherapy)ª¤
Adjuvant EBRT and IORT have been used alone and in combination in the adjuvant setting (Table 2)^{£Û21,32,53-60£Ý}. The majority of studies indicate that EBRT alone or in combination with IORT has a significant survival advantage over the use of IORT alone. In a randomized trial IORT was observed to reduce the local recurrence rate by 50% following surgery, but this did not translate into a significant survival advantage (3-year survival with IORT=7% vs no IORT 3%)^£Û21£Ý. In selected patients IORT and resection produced 3 and 5-year survival rates of 53% and 29%^{£Û61,62£Ý}. The use of IORT however requires specialised facilities and can be associated with severe complications.ª¥
          EBRT (with concomitant chemotherapy) following resection is generally well tolerated but the degree of survival advantage, if any, is uncertain. To address this issue a multicentre Phase ¢ó trial organized by the European Organisation for Research and Treatment of Cancer (EORTC) compared chemoradiotherapy in patients following potentially curative surgery for pancreatic cancer with surgery alone^£Û58£Ý. Between 1987 and 1995, 218 patients were randomized to receive either chemoradiotherapy or no chemoradiotherapy following curative surgery for pancreatic or ampullary cancer. Ninety-three out of 110 patients randomized to treatment received a total of 40 Gy with concomitant continuous infusion of 5-FU. There were a total of 54 patients in the observation group and 60 patients in the treatment group with pancreatic ductal adenocarcinoma. There was no significant difference in median survival (with treatment 17ª±1 months vs 12.6 months with observation) and in five year survival £Ûwith treatment 20 (95% CI, 5-35)% ª«vsª« 10 (0-20)% with observation£Ý. Similarly there was no significant difference in survival between the treatment and observation groups in patients with ampullary cancer. This study showed that there was no survival advantage for adjuvant chemoradiotherapy for pancreatic and ampullary cancer but has been criticized because it was almost certainly underpowered.ª¤

REGIONAL THERAPYª¤

Advanced pancreatic cancerª¤
Regional therapy has been developed with the objective of delivering high doses of cytotoxic drug to the tumour. The systemic side effects should be reduced with this approach. The coeliac and hepatic arteries and portal vein have all been used to deliver chemotherapeutic drugs to the tumour bed. Good control of hepatic metastases has been reported, with disease progression mainly due to local progression or peritoneal deposits. The combination of 5-FU, folinic acid and cisplatin produced median survival times of 9-14 months in selected patients^{£Û63,64£Ý}.  It has also been reported that some apparently irresectable tumours have become resectable following regional therapy^£Û64£Ý.ª¤ª¤

Adjuvant regional therapy
There have been several studies which have demonstrated improved survival in patients receiving regional chemotherapy following pancreatic resection largely in comparison with historical controls (Table 3)^{£Û65-68£Ý}. Link ª«et al^£Û69£Ý found a median survival of 21 months in 18 patients who had undergone pancreatoduodenectomy for pancreatic ductal adenocarcinoma and then coeliac artery infusion of 5-FU, folinic acid, mitoxantrone and cisplatin compared to 9.3 months for historical controls. Disease progression occurred principally locally or in the peritoneum and was rarely detected in the liver. The rate of hepatic recurrence was greatly reduced using a combination of hepatic artery and portal vein infusion in patients with resected pancreatic, which in one study cancer produced a 54% three-year survival compared to 34% in historical controls^£Û65£Ý. Ozaki et al^£Û66£Ý found a 5-year survival rate of 32% patients treated with extended resection, IORT and hepatic artery and portal vein. The encouraging results of these small studies have prompted the ESPAC-2 trial, which is a multicentre, prospective randomized controlled Phase ¢ó trial. This study will compare adjuvant intra-arterial chemotherapy (cisplatin, 5-FU, folinic acid and mitoxantrone) and radiotherapy (Arm A) with surgery alone (Arm B) in patients who have undergone potentially curative resection for pancreatic ductal adenocarcinoma or ampullary carcinoma. The trial will recruit 110 patients into each arm and will be completed by 2007 aiming to provide a definitive answer to the role of adjuvant regional therapy for
pancreatic cancer.

Table 1 Survival following surgery and adjuvant chemotherapy for pancreatic cancerª¤  

5-FU = 5-fluorouracil; DOX = doxorubicin; MMC = mitomycin C; * randomised cont rolled trial, PDAC = pancreatic ductal adenocarcinoma.

Table 2 Survival following surgery and radiotherapy for pancreatic cancerª¤

EBRT = external beam radiotherapy; IORT = intraoperative radiotherapy; nm = nega tive resection margin; pm = positive resection margin; pdc = pancreatic ductal adenocarcinoma.ª¤ª¤  

Table 3 Adjuvant regional therapy for pancreatic cancerª¤  

HAI = hepatic arterial infusion; PVI = portal vein infusion; CAI = coeliac artery infusionª¤  

NEOADJUVANT THERAPYª¤  

The rationale for pre-operative therapy includes (a) the avoidance of long delays following surgery before starting adjuvant therapy and (b) an attempt to downstage the tumour and thereby increase the prospect of resection (Table 4) ^{£Û70-77£Ý}. Pre-operative radiotherapy produced only modest increases in resectability and so chemotherapy was added in an attempt to improve the efficacy of this approach. Recent studies have reported resection rates as high as 60%^{£Û70-77£Ý} but not surprisingly those tumours £¾4cm-cm, encase the superior mesenteric artery or obstruct the superior mesenteric/ hepatic portal vein are less likely to be resected^{£Û71,73£Ý}. Pre-operative chemoradiotherapy may also increase the incidence of clear resection margins to as high as 90%, compared to the accepted norm of 60%-80%.ª¥  
         The effect of any long-term survival benefit from neoadjuvant treatment, if any, is not known due to the lack of randomized controlled studies. Twenty- four out of 53 patients with pancreatic ductal adenocarcinoma initially treated with 5-FU, mitomycin C and 50.4 Gy were able to undergo resection with a medi an survival of 15.7 months^£Û74£Ý. There was a significant level of toxicity associated with this regimen with two treatment related deaths. Another recent non-randomized study found a median survival of 19.2 months for patients with pancreatic cancer treated by pre-operative chemoradiation compared to 22 months for those treated by post-operative chemoradiation. Neither survival nor the pattern disease of recurrence was significantly different between the two groups^£Û73£Ý.ª¤ª¤  

COMBINATION THERAPYª¤  

Advanced pancreatic cancerª¤  
The combination of chemoradiation and follow-on chemotherapy may enable good local control with systemic destruction of the disease. The Gastrointestinal-Tumour Study Group (GITSG) randomized patients with advanced pancreatic cancer to receive either 60Gy EBRT (with radiosensitizing 5-FU) with or without follow -on 5-FU versus 40Gy EBRT with radiosensitizing 5-FU and follow-on 5-FU. The median survival times were 40, 23 and 42 weeks respectively, indicating a- likely valuable role for radiosensitizing (¡À follow-on)chemotherapy but not for increased radiotherapy^£Û78£Ý. Other combinations have been evaluated in the palliative setting^£Û79£Ý. A randomized trial of IORT versus IORT and methotrexate/5-FU produced a median survival of 4.8 and 8.5 months respectively^£Û80£Ý. 

Adjuvant combination therapyª¤
The regimen originally adopted by the GITSG for patients with advanced pancreatic cancer was used in the adjuvant setting for a randomized trial in the 1970¡äs . Forty-three patients were randomized to receive either 40Gy (with radiosensitizing 5-FU) then weekly 5-FU or surgery alone. The median survival in the treated group was 20 months compared to 11 months in the surgery only group and the two year survival rates were 42% and 15% respectively^£Û81£Ý. To increase numbers in the treatment group a further 30 patients received adjuvant therapy. The median survival was 18 months with a two year survival of 46%^£Û82£Ý. The number of patients that received treatment as part of the randomized study however was far too small for convincing conclusions to be drawn. The results were encouraging enough for other studies to adopt this protocol and investigate its role in the treatment of pancreatic cancer 
(Table 5)^{£Û81-88£Ý}. Yeo et al^£Û84£Ýcompared three different regimens in selected patients who had undergone pancrea toduodenectomy: ¢Ù 40-45Gy EBRT plus follow-on 5-FU for 4 months (standard); ¢Ú 50-57Gy EBRT plus hepatic radiation plus 5-FU + folinic acid for 4 months (intensive); ¢Û no adjuvant treatment. The median survival was 21 months and the two-year survival was 44% for the group given standard adjuvant treatment, significantly better compared to 13.5 months and 30%, respectively in the no treatment group. There was no significant survival difference however between patients that had received the intensive treatment and those that had received no treatment. The main drawbacks to this study are the retrospective data that suffer from patient selection bias and no specification of patient performance status, which is an extremely important independent prognostic factor.ª¥  
          A phase ¢ó randomized controlled study organised by the Radiation Therapy Oncology Group (RTOG) in the USA is currently recruiting patients who have undergone resection for pancreatic adenocarcinoma. This study aims to compare 5-FU versus  gemcitabine pre- and post- chemoradiotherapy all following surgery. The trial  has already accrued the original 330 patient target but is still recruiting, presumably because of a lack of a significant therapeutic effect so far.ª¥  
         The UK Pancreatic Cancer Trials Group (UKPACA)^£Û85£Ý utilized the GITSG protocol for an open phase II study of 40 patients (34 with pancreatic ductal adenocarcinoma and 6 with ampullary tumour) who had undergone-pancreatoduodenectomy between 1987 and 1993 were recruited. Patients received 40Gy (with 5-FU as a radiosensitizer) plus 5-FU weekly for a maximum of 24 weeks. After a median of eight treatments there were no treatment related deaths and no hospitalizations even with a prolonged course of post-operative chemotherapy. The median survival for patients with pancreatic ductal adenocarcinoma was 13.2 months and the  five-year survival rate was 15%.ª¥  
         The findings of these studies were instrumental in the design of the ESPAC-1 trial, which commenced in 1994. This trial was established to compare the effects of three adjuvant treatments with a control group. The four groups were: ¢Ù chemoradiotherapy (40Gy with radiosensitizing 5-FU); ¢Ú chemotherapy (5-FU plus folinic acid for six months); ¢Û combination chemoradiotherapy followed by chemotherapy; and ¢Ü best supportive care. Patients were eligible following potentially curative resection for pancreatic ductal adenocarcinoma. Between February 1994 and April 2000 a total of 591 patients were randomized of which 541 had pancreatic ductal adenocarcinoma. A total of 61 centres recruited patients from UK, Ireland, France, Sweden, Spain, Italy, Germany, Switzerland, Greece,  Hungary, Belgium and Austria.  Randomization was stratified by resection margin status. Clinicians could randomize patients into a 2¡Á2 factorial design (obse rvation, chemoradiation, chemotherapy or combination) or into one of the main treatment comparisons ª©(i.e.ªª chemoradiation vs control or chemotherapy vs control). Two-hundred and eighty five patients were randomized to the 2¡Á2 factorial design, a further 68 patients were randomized to chemoradiation vs no chemoradiation and 188 patients were randomized to chemotherapy vs  no chemotherapy. Tumour grade, size, nodal status and resection margin status were all significantly associated with survival. The overall results showed no benefit for chemoradiation vs no chemoradiation (median survival 15.5 months vsª«16.2 months respectively). There was evidence of a survival benef it for chemotherapy (median survival 19.7 months) compared to those patients 
who did not receive chemotherapy (median survival 14 months). The effect was reduced when taking into account whether patients had also received chemoradiation suggesting that chemoradiation may decrease the benefit of chemoth erapy^£Û89£Ý. Moreover quality of life analysis showed no significant difference between any of the groups indicating that adjuvant therapy in pancreatic cancer is worthwhile, provided there is a significant prolongation of life^£Û90£Ý.ª¥  
            The results of ESPAC-1 have provided for the first time a clear indication of a potential benefit for the use of chemotherapy in the treatment of pancreatic cancer. Even more importantly both ESPAC-1 and the EORTC trials have rejected the use of chemoradiation as adjuvant therapy in pancreatic cancer. Thus the focus of future studies such as ESPACª²3 will be on new and efficacious chemothe rapy regimens. This study is randomizing patients to three arms: 5-FU+folinic acid, gemcitabine and observation. The power of the study is such to detect a 10% difference in 2-year survival between any of the groups. Thus ESPAC-3 will establish (a) the benefit of adjuvant chemotherapy for pancreatic cancer and (b) if such, then the best form of chemotherapy.

Table 4 Neoadjuvant therapy for pancreatic cancerª¤  

EBRT = external beam radiotherapy; 5-FU = 5-fluorouracil; MMC= mitomycin C; IORT = intraoperative radiotherapy; STP = streptozocin; CDDP = cisplatinum; FA = folinic acid; DPD = dipyridamole; n = number; CPP=cisplatin; NR = not resectable.  

Table 5 Results of combination therapy in patients who have undergone resection for pancreatic cancerª¤  

EBRT = external bean radiotherapy; 5-FU = 5-fluorouracil; FA = folinic acid; CPP = cisplatinª¤ª¤ª¤  

CONCLUSIONª¤  

This is a very encouraging time for the treatment of pancreatic cancer. The results of these large European trials have at last given clear indications for future therapies of pancreatic cancer. By using this information, reasoned approaches are being developed to improve the treatment of patients with pancreatic cancer without sacrificing quality of life.ª¤ª¤  

AKNOWLEDGEMENTS We are grateful to the Cancer Research campaign, UK for funding the ESPAC-1 and ESPAC-3 trials of adjuvant treatments in pancreatic cancer.ª¤ª¤  

REFERENCES

1  HMSO. Great Britain Office of Population Censuses and Surveys: Cancer Statistics. London (1998)
2  Parkin DM, Muir CS, Whelan SL, Sao YT, Ferlay J, Powell (eds). Cancer incidence in five continents (Vol ¢ö). Lyon:
    International Agency for Research on Cancer  (IARC Scientific Publications No. 129). Oxford: Oxford University Press, 1992
3  Neoptolemos JP, Russell RCG, Bramhall SR, Theis B. Low mortality following resection for pancreatic and periampullary tumours
    in 1026 patients: UK survey of specialist pancreatic units. Br J Surg, 1997;84:1370-1376
4  Bramhall SR, Allum WH, Jones AG, Allwood A, Cummins C, Neoptolemos JP. Incidence treatment and survival in 13,560 patients
    with pancreatic cancer: an epidemiological study in the West Midlands. Br J Surg, 1995;82:111-115
5  Wade TP, Halaby IA, Stapleton DR, Virgo KS, Johnson FE. Population based analysis of treatment of pancreatic cancer and
    Whipple resection: Department of Defence hospitals 1989-1994. Surgery, 1996;120:680-687
6  Trede M, Schwall G, Saeger HD. Survival after pancreatoduodenectomy: 118 consecutive resections without an operative
    mortality.  Ann Surg, 1990;211:447-458
7  Cameron JL, Pitt HA, Yeo CJ, Lillimoe KD, Kaufman HS, Coleman J. One hundred forty five consecutive
    pancreaticoduodenectomies without mortality. Ann Surg, 1993;217:430-438
8  Yeo CJ, Cameron JL, Lillimoe KD, Sitzman JV, Hiruban RH, Goodman SN, Dooley WC, Coleman J, Pitt HA. Pancreatoduodenectomy
    for cancer of the head of the pancreas in 201 patients.  Ann Surg, 1995;221:721-733
9  Ishikawa O, Ohigashi H, Sasaki Y, Kabuto T, Fukunda I, Furukawa H, Imaoka S, Iwanaga T. Practical usefulness of lymphatic
    and connective tissue clearance for the carcinoma of the pancreas head. Ann Surg, 1998;208:215-220
10  Nitecki SS, Sarr MG, Colby TV, Van Heerden JA. Long term survival after resection for ductal adenocarcinoma of the pancreas.
      It is really improving? Ann Surg,  1995;221:59-66
11  Nagakawa T, Nagamori M, Futakami F, Tsukioka Y, Kayahara M, Ohta T, Ueno K, Miyazaki I. Results of extensive surgery
     for pancreatic carcinoma. Cancer, 1996;77:640-645
12  Sperti C, Pasquali C, Piccoli A, Pedrazzolli S. Survival after resection for ductal adenocarcinoma of the pancreas.
      Br J Surg, 1996;83:625-663
13  Ohigashi H, Ishikawa O, Tamura S, Imaoka S, Sasaki Y, Kameyama M, Kabuto T, Furukawa H, Hiratsuka M, Fujita M,
      Hashimoto T, Hosomi N, Kuroda C. Pancreatic invasion as the prognostic indicator of duodenal adenocarcinoma reated
      by pancreatoduodenectomy plus extended lymphadenectomy. Surgery, 1998;124:510-515
14  Kayahara M, Nagakawa T, Ueno K, Ohta T, Takeda T, Miyazaki I. An evaluation of radical resection for pancreatic cancer based
      on the mode of recurrence as determined by autopsy and diagnostic imaging. Cancer, 1993;72:2118-2123
15  Satake K, Nishiwaki H, Yokomatsu H.  Surgically curability and prognosis for standard versus extended resection for T1 carcinoma
      of the pancreas. Surg Gynecol Obstet, 1992;175:259
16  Pedrazzoli S, Dicarlo V, Dionigi R, Mosca F, Pederzoli P, Pasquali C, Kloppel G, Dhaene K, Michelassi F. Standard versus
      extended lymphadenectomy associated with pancreatoduodenectomy. In the surgical treatment of adenocarcinoma of the
      head of the pancreas: a Multicenter, prospective, randomized study. Lymphadenectomy study group. 
     Ann Surg,  1998;228:508-517
17  Jones L, Russell RCG, Mosca F, Boggi U, Sutton R, Slavin J, Hartley M, Neoptolemos JP. Standard
      Kausch-Whipple pancreatoduodenectomt. Dig Surg,  1999:297-304
18  Di Carlo V, Zerbi A, Balzano G, Corso V. Pylorus preserving pancreaticoduodenectomy versus conventional Whipple operation.
      World J Surg, 1999;23:920-925
19  Whittington R, Bryer MP, Haller DG, Solin LJ, Rosato EF. Adjuvant therapy of resected adenocarcinoma of the pancreas.
      Int J Radiat Oncol Biol Phys,1991;21:1137-1143
20  Westerdhal J, Andren Sandberg ?, Ihse I. Recurrence of exocrine pancreatic cancer local or hepatic? Hepato
      Gastroenterology,  1993;40:384-387
21  Zerbi A, Fossati V, Parolini D, Carlucci M, Balzano G, Bordogna G, Staudacher C, Di Carlo V. Intraoperative radiation therapy
     adjuvant to resection in the treatment of pancreatic cancer. Cancer, 1994;73:2930-2935
22  Sperti C, Pasquali C, Piccoli A, Pedrazzolli S. Recurrence after resection for ductal adenocarcinoma of the pancreas.
      World J Surg, 1997;21:195-200
23  Griffin JF, Smalley SR, Jewell W, Paradelo JC, Reymond RD, Hassanein RES, Evans RG. Patterns of failure after curative resection
      of pancreatic carcinoma. Cancer, 1990;66:56-61
24  Amikura K, Kobari M, Matsuno S. The time of occurrence of liver metastasis in carcinoma of the pancreas.
      Int J Pancreatol,  1995;17:139
25  Nagakawa T, Konishi I, Ueno K, Ohta T, Kayahara M. A clinical study on lymphatic flow in carcinoma of the pancreatic
      head area-peripancreatic regional lymph node grouping.  Hepatogastroenterol, 1993;40:457-462
26  McCarthy M, Evans J, Sagar G, Neoptolemos JP. Prediction of resectability of pancreatic malignancy by computed tomography.
      Br J Surg, 1998;85:320-325
27  Fern¨¢ndez-Del Castillo C. Further experience with laparoscopy and peritoneal cytology in the staging of pancreatic cancer.
      Br J Surg, 1995;82:1127-1129
28  Edge SB, Schmieg R Jr, Rosenlof LK, Willheim MC. Pancreas cancer resection outcome in American university centers
      in 1989-1990. Cancer, 1993;71:3502
29  Wade TP, Kraybill WG, Virgo KS, Johnson FE. Pancreatic cancer treatment in the United States Veteran from 1987-1991ª²
      effect of tumour stage on survival.  J Surg Oncol, 1995;58:104-111
30  Millikan KW, Deziel DJ, Silverstein JC, Kanjo TM, Christein JD, Doolas A, Prinz RA. Prognostic factors associated with
      resectable adenocarcinoma of the head of the pancreas. Am Surg, 1999;65:618-623
31  Allema JH, Reinders ME, Vangulik TM, Koelemay MJW, Vanleeuwen DJ, Dewit LT, Gouma DJ, Obertop H. Prognostic factors
      for survival after pancreaticduodenectomy for patients with carcinoma of the pancreatic head region.
      Cancer, 1995;75:2069-2076
32  Willett CG, Lewandrowski K, Warshaw AL, Efird J, Compton CC. Resection margins in carcinoma of the head of the
      pancreas. Implications for radiation therapy.  Ann Surg, 1993;217:144-148
33  Haycox A, Lombard M, Neoptolemos JP, Walley T. Review article: current treatment and optimal patient managemant in
      pancreatic cancer.  Aliment Pharmacol Ther, 1998;12:949-964
34  Nagourney RA, Eckerling G, Atiba J, Iyer P. PALA plus 5-fluorouracil (5-FU) and low dose leucovorin (LDLV) in advanced gastric
     and pancreatic cancer:a phase ¢ò trial.  Proc Am Soc Clin Oncol, 1992;11:582
35  Knuth A, Bernhard H, Klein O, Meyer zum Buschenfelde KH. Combination fluorouracil, folinic acid and interferon alpha-2a:
      An active regimen in advanced pancreatic carcinoma. Semin Oncol, 1992;19(Suppl 3):211-214
36  Moore MJ, Andersen J, Burris H, Tarassoff P, Green M, Casper E. A randomised trial of gemcitabine versus 5-FU as first line therapy
      in advanced pancreatic cancer.  J Clin Oncol, 1997;15:2403
37  Sauer-Heilborn A, Kath R, Schneider CP, Hoffken K. Severe non-haematological toxicity after treatment with gemcitabine.
      J Cancer Res Clin Oncol, 1999;125:637-640
38  Mallinson CN, Rake MD, Cocking JB, Fox CA, Cwynarski MT, Diffey BL, Jackson Hanley J, Wass VJ. Chemotherapy in pancreatic
      cancer: results of a controlled prospective randomised, multicentre trial. Br J Med,  1980;281:1589-1591
39  Cullinan S, Moertel CG, Wieand HS, Schutt AJ, Krook JE, Foley JF, Norris BD, Kardinal CG, Tschetter LK, Barlow JF. A phase ¢ó trial
      on the therapy of advanced pancreatic cancer.  Cancer, 1990;65:2207-2212
40  Frey C, Twomey P, Keehn R, Elliot D, Higgins G. Randomized study of 5-FU and CCNU in pancreatic cancer: Report of the
      veterans adminstration surgical adjuvant cancer chemotherapy study group. Cancer, 1980:27-31
41  Palmer KR, Kerr M, Knowles G, Cull A, Carter DC, Leonard RCF. Chemotherapy prolongs survival in operable pancreatic carcinoma. 
      Br J Surg, 1994;81:882-885
42  Glimelius B, Hoffman K, Sj¢id¨¦n PO, Jacobsson G, Sellstrm H, Enander LK. Chemotherapy improves survival and quality of life
      in advanced pancreatic and biliary cancer.  Ann Oncol,  1996;7:593-600
43  Splinter TA, Obertop H, Kok TC, Jeekel J. Adjuvant chemotherapy after resection of adenocarcinoma of the periampullary region
     and the head of the pancreas. A nonrandomised pilot study. J Cancer Res Clin Oncol, 1989;115:200-202
44  Livingstone EH, Welton ML, Reber HA. Surgical treatment of pancreatic cancer: the United States experience. 
      Int J Pancreatol,  1991;9:153-157
45  Bakkevold KE, Arnesjo B, Dahl O, Kambestad B. Adjuvant combination chemotherapy (AMF) following radical resection of
     carcinoma of the pancreas and papilla of Vaterª²results of a controlled, prospective, randomised multicentre study.
     Eur J Cancer,  1993;5:698-703
46  Baumel H, Huguier M, Manderscheid JC, Fabre JM, Houry S, Fagot H. Results of resection for cancer of the exocrine pancreas:
     a study from the French Association of Surgery. Br J Surg,  1994;81:102-107
47  Gunderson LL, Nagorney DM, Martenson JA, Donahue JH, Gorton GR, Nelson H. External beam plus intraª²operative irradiation
      for gastrointestinal cancers.  World J Surg,  1995;19:191-197
48  Tisdale BA, Paris KJ, Lindberg RD, Jose B, Spanos WJ. Radiation therapy for pancreatic cancer-A retrospective study of the
      University of Louisville experience.  South Med J,  1995;88:741-744
49  Komaki R, Wadler S, Peters T. High dose local irradiation plus prophylactic hepatic irradiation and chemotherapy for
      inoperable adenocarcinoma of the pancreas: a preliminary report of a multiinstitutional trial (radiation therapy oncology
      group protocol 8801). Cancer, 1992;69:2807-2812
50  Gunderson LL, Martin JK, Kvols LT. Intraoperative and external beam irradiation ¡À 5FU for locally advanced pancreatic cancer.
      Int J Radiat Oncol Biol,  1987;13:319-325
51  Garton GR, Gunderson LL, Nagorney DM, Donohue JH, Martin JK, McIlrath DC, Cha SS. High dose preoperative external beam
     and introperative irradiation foe locally advanced pancreatic cancer. Int J Radiation Oncol Biol Phys, 1993;27:1153-1157
52  Willett C, Warshaw A. Intraoperative radiation therapy of pancreatic cancer. In: Beger H, Warshaw A, B¨¹chler M,
     Carr-Locke D, Neoptolemos JP, Russell C, Sarr M, eds. Oxford: The Pancreas. Blackwell Science Ltd, 1998
53  Johnstone PA, Sindelar WF. Patterns of disease recurrence following definitive therapy of adenocarcinoma of the pancreas
      using surgery and adjuvant radiotherapy correlations of a clinical trial. Int J Radiat Oncol Biol Phys, 1993;27:831-834
54   Di Carlo V, Zerbi A, Balzano G, Villa E. Intraoperative and postoperative radiotherapy in pancreatic cancer.
      Int J Pancreatol,  1997;21:53-57
55  Dobelbower RR, Merrick HW, Khuder S, Battle J, Herron L, Pawlicki T. Adjuvant radiation therapy for pancreatic cancer: a
     15 year experience.  Int J Radiat Oncol Biol Phys, 1997;39:31
56  Farrell TJ, Barbot D, Rosato F. Pancreatic resection combined with intraoperative radiation therapy for pancreatic cancer. 
     Ann Surg, 1997;226:66
57  Hishinuma S, Ogata Y, Matsui J, Ozawa I. Results of surgery and adjuvant radiotherapy for pancreatic cancer.
     J Hepatobiliary Pancreat Surg, 1998;5:143-150
58  Klinkenbijl JH, Jeekel J, Sahmoud T, van Pel R, Couvreur ML, Veenhof CH. Adjuvant radiotherapy and 5ª²fluorouracil after
     curative resection of cancer of the pancreas and periampullary region. Phase ¢ó trial of the EORTC gastrointestinal tract
     cancer cooperative group. Ann Surg,  1999;230:776-784
59  Mehta VK, Fisher G, Ford J, Oberhelman H, Vierra M, Bastidas A. Adjuvant radiotherapy and concomitant 5ª²fluorouracil by
      protracted venous infusion for resected pancreatic cancer. Int J Radiat Oncol Biol Phys,  2000;48:1483-1487
60  Lee J, Whittington R, Williams N, Berry M, Vaughn D, Haller D. Outcome of pancreaticoduodenectomy and impact of
     adjuvant therapy for ampullary carcinomas. Int J Radiat Oncol  Biol Phys,  2000;47:945-953
61  Hiraoka T. Extended radical resection of cancer of the pancreas with intraoperative radiotherapy.
      Balli¨¨re's Clin Gastroenterol, 1990;4:985-993
62  Ozaki H, Kinoshita T, Kosuge T, Egawa S, Kishi K. Effectiveness of multimodality treatment for resectable pancreatic cancer.
      Int J Pancreatol, 1990;7:195
63  Aigner KR, Muller H, Bessermann R. Intra-arterial chemotherapy with MMC, CDDP and 5-FU for non-resectable pancreatic
      acncer - A phase ¢ò study. Reg Cancer Treat, 1990;3:1-6
64  Muchmore JH, Preslan JE, George WJ. Regional chemotherapy for inoperable pancreatic carcinoma.
      Cancer, 1996;78(Suppl):664-673
65  Ishikawa O, Ohigashi H, Sasaki Y, Furukawa H, Kabuto T, Kameyama M, Nakamori S, Hiratsuka M, Imaoka S. 
      Liver perfusion chemotherapy via both the hepatic artery and portal vein to prevent hepatic metastasis after
      extended pancreatectomy for adenocarcinoma of the pancreas. Am J Surg, 1994;168:361-364
66  Ozaki H. Modern surgical treatment of pancreatic cancer. Int J Pancreatol, 1994;16:121-129
67  Link HK, Gansauge F, G¢irich J, Leder GH, Rilinger N, Beger HG. Palliative and adjuvant regional chemotherapy in pancreatic
      cancer. Eur J Surg Oncol, 1997;23:409-414
68  Beger HG, Gansauge F, Buchler MW, Link KH. Intraarterial adjuvant chemotherapy after pancreaticoduodenectomy for
      pancreatic cancer: significant reduction in occurrence of liver metastasis.  World J Surg,  1999;23:946
69  Link KH, Gansauge F, Pillasch J, Rilinger N, B¨¹chler M, Beger HG. Regional treatment of advanced nonresectable and of
      resected pancreatic cancer via celiac axis infusion. First results of a single institution study. Dig Surg,  1994;11:414-419
70  Ishikawa O, Ohigashi H, Imaoka S, Sasaki Y, Iwanaga T, Matayoshi Y, Inoue T. Is the long term survival rate improved
      by preoperative irradiation prior to Whipple¡äs procedure for adenocarcinoma of the pancreatic head? 
     Arch Surg, 1994;129:1075-1080
71  Coia L, Hoffman J, Schier R, Weese J, Solin L, Weiner L, Eisenberg B, Paul A, Hanks G. Preoperative chemoradiation
      for adenocarcinoma of the pancreas and duodenum.  Int J Radiat Oncol Biol Phys, 1994;30:161-167
72  Staley CA, Lee JE, Clearly KR, Abbruzzese JL, Fenoglio CJ, Rich TA, Evans DB. Preoperative chemoradiation
      pancreaticoduodenectomy and intraoperative radiation therapy for adenocarcinoma of the pancreatic head.
      Am J Surg,  1996;171:118-124
73  Spitz FR, Abbruzzese JL, Lee JE, Pisters PWT, Lowy AM, Fenoglio CJ. Preoperative and postoperative chemoradiation strategies
      in patients treated with pancreaticoduodenectomy for adenocarcinoma of the pancreas.  J Clin Oncol,  1997;15:928
74   Hoffman JP, Lipsitz S, Pisansky T, Weese JL, Solin L, Benson AB 3rdªª. Phase ¢ò trial of preoperative radiation therapy
      and chemotherapy for patients with localized, resectable adenocarcinoma of the pancreas: an eastern cooperative
      oncology group study. J Clin Oncol,  1998;16:317-323
75  White R, Lee C, Anscher M, Gottfried M, Wolf R, Keogan M. Pre-operative chemoradiation for patients with locally
      advanced adenocarcinoma of the pancreas.  Ann Surg Oncol, 1999;6:38-45
76  Wanebo H, Glicksman A, Veizeridis M, Clark J, Tibbetts L, Koness R, Levy Y. Preoperative chemoradiotherapy and surgical resection
      of locally advanced pancreatic cancer.  Arch Surg, 2000;135:81-87
77  Snady H, Bruckner H, Cooperman A, Paradiso J, Kiefer L. Survival advantage of combined chemoradiotherapy compared
      with resection as the initial treatment of patients with regional pancreatic carcinoma. Cancer, 2000;89:314-327
78  Gastrointestinal Tumour Study Group. Therapy of locally unresectable pancreatic carcinoma: A randomised comparison of high
      dose (6000 rads) radiation alone, moderate dose radiation (400 rads + 5-Fluorouracil), and high dose
      radiation + 5-Fluorouracil. Cancer, 1981;48:1705-1710
79  Prott FJ, Schonekaes K, Preusser P, Ostkamp K, Waagner W, Micke O, Potter R, Sulkowski U, Rube C, Berns T, Willich N.
      Combined modality treatment with accelerated radiotherapy and chemotherapy in patients with locally advanced
      inoperable carcinoma of the pancreas: Results of a feasibility study. Br J Cancer, 1997;75:597-601
80  Yasue M, Sakamoto J, Yasui K, Morimoto T, Miyashi S, Kurimoto K. A randomised trial of intraoperative radiation therapy
      (IORT) vs IORT plus chemotherapy (MTX-5FU) for adenocarcinoma of the pancreas. Cancer Res Ther Control,  1993;3:283
81   Kalser MH, Ellenberg SS. Pancreatic cancer :Adjuvant combined radiation and chemotherapy following curative resection.
      Arch Surg, 1985;120:899-903
82  Douglass HO. Further evidence of effective adjuvant combined radiation and chemotherapy following curative resection of
      pancreatic cancer. Cancer, 1987;59:2006
83  Conlon KC, Klimstra DS, Brennan MF. Long term survival after curative resection for pancreatic ductal
      adenocarcinoma. Clinicopathologic analysis of 5 year survivors. Ann Surg,  1996;223:273-279
84  Yeo C, Abrams R, Grochow L, Sohn T, Ord S, Hruban R. Pancreaticoduodenectomy for pancreatic adenocarcinoma:
      postoperative adjuvant chemoradiation improves survival: a prospective, single institution experience.  Ann Surg, 1997;225:621
85  Neoptolemos JP. Adjuvant radiotherapy and follow on chemotherapy in patients with pancreatic cancer: results of the UK
      Pancreatic Cancer Study Group (UKPACA-1). GI Cancer, 1998;2:235-245
86  Abrams RA, Grochow LB, Chakravarthy A, Sohn TA, Zahurak ML, Haulk TL, Ord S, Hruban RH, Lillemoe KD, Pitt HA, Cameron JL,
      Yeo CJ. Intensified adjuvant therapy for pancreatic and periampullary adenocarcinoma: survival results and observations
      regarding patterns of failure, radiotherapy dose and CA19-9 levels. Int J Radiat Oncol Biol Phys, 1999;44:1039-1046
87  Paulino A. Resected pancreatic cancer: treatment with adjuvant radiotherapy with or without 5-FU treatment results and patterns
      of failure.  Am J Clin Oncol, 1999;22:489-494
88  Andr¨¦ T, Balosso J, Louvet C, Hannoun L, Houry S, Hughier M. Combined radiotherapy and chemotherapy (cisplatin and 5-FU)
      as palliative treatment for localised unresectable or adjuvant treatment for resected pancreatic adenocarcinoma: results of a
      feasibility study. Int J Radiation Oncology Biol Phys, 2000;46:903-911
89  Neoptolemos JP, Dunn JA, Moffitt DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pedezoli P, Dervenis C, Fernandez-Cruz L,
      Lacaine F, Pap A, Spooner D, Kerr DJ, Freiss H, B¨¹chler M. ESPAC-1: A European Randomised controlled study of
      adjuvant chemoradiation and chemotherapy in resectable pancreatic cancer.  Lancet,  2001 (in press)
90  Neoptolemos JP, Moffitt DD, Dunn JA, Almond J, Beger HG, Link KH, Pederzoli P, Bassi C, Dervernis C, Fernandezª²Cruz L,
      Lacaine F, Spooner D, Kerr DJ, Friess H, B¨¹chler.  Survival, quality of life and qualityª²adjusted survival of patients in the ESPAC-1
      trial: a European randomized trial to assess the roles of adjuvant chemotherapy and chemoradiation in resectable pancreatic
      cancer.  Brit J Surg,  2001;88:31