European Study Group For Pancreatic Cancer Research Articles

Evaluating the Impact of ESPAC-1 on Shifting the Paradigm of Pancreatic Cancer Treatment

BackgroundIn 2004, the European Study Group for Pancreatic Cancer (ESPAC)-1 long-term data concluded that adjuvant chemotherapy provided a survival benefit for patients with pancreatic ductal adenocarcinoma (PDAC), whereas adjuvant chemoradiation was associated with worse overall survival. In this study, we investigated how long it took for US practice patterns to change following this trial. MethodsThe National Cancer Database was used to identify patients with stage I-III PDAC who underwent R0 or R1 resection followed by adjuvant chemotherapy or chemoradiation between 1998 and 2015. A multivariate analysis was performed to determine predictors of receiving adjuvant chemoradiation in the post-ESPAC-1 era. ResultsBetween 1998 and 2015, adjuvant chemotherapy use increased from 2.9% to 51.6%, whereas adjuvant chemoradiation decreased from 49.5% to 22.9%. In 2010, adjuvant chemotherapy utilization surpassed that of chemoradiation. For patients diagnosed in the post-ESPAC-1 era, adjuvant chemotherapy (n = 7733) and chemoradiation (n = 6969) groups were compared. Patients who underwent adjuvant chemoradiation were younger, had private insurance, underwent surgery at nonacademic centers, and had more pathologically advanced cancers (all P < 0.01). After 2010, R1 resection was the strongest independent predictor of adjuvant chemoradiation use by multivariate analysis (OR 2.05, CI 1.8-2.3, P < 0.01). ConclusionsAdjuvant chemotherapy use exceeded that of adjuvant chemoradiation 6 y after the final publication of ESPAC-1 in 2004, highlighting the challenges of disseminating and adopting clinical data. After 2010, R1 disease was the most significant predictor of receiving adjuvant chemoradiation. Prospective studies are underway to definitively address the role of adjuvant chemoradiation in PDAC.

Adjuvant and neoadjuvant chemotherapy in pancreatic ductal adenocarcinoma

Abstract The management of pancreatic cancer has dramatically changed since the first major randomized trial published in 2001 by the European Study Group for Pancreatic Cancer (ESPAC) stimulated the development of multimodality oncosurgical therapies. ESPAC-1 demonstrated a survival improvement from upfront surgery of only 8%, increasing to 21% 5-year survival for 5-fluorouracil/folinic acid but only 10.8% for chemoradiotherapy. ESPAC-4 has shown a 5-year survival rate of 30% for all patients without restriction of 30% using a combination of gemcitabine and capecitabine, rising to 40% in those with an R0 resection margin, or nearly 50% in those with N0 lymph node status. In selected patients with favorable prognostic features mFOLFIRINOX can produce a 50% 5-year survival rate but with added toxicity. While a positive resection margin is associated with an increased likelihood of local recurrence, this of itself is not the contributor to reduced survival, but rather reflects the increased probability of systemic disease. Thus, strategies aimed at local control, may reduce subsequent local progression, but will not improve overall survival. Neoadjuvant chemotherapy is increasingly utilized in cases of borderline resectable or locally advanced pancreatic cancer, but there is still a lack of proof of concept studies. High-quality evidence from randomized controlled trials to identify the indications and benefits of neoadjuvant therapy in pancreatic cancer are required. The use of patient-derived tumor organoids may predict response to chemotherapy which could open a new opportunity in pancreatic cancer treatment, stratifying patients into treatment groups based on their response to these therapies in the laboratory.

Cathepsin D Expression and Gemcitabine Resistance in Pancreatic Cancer.

BackgroundCathepsin-D (CatD), owing to its dual role as a proteolytic enzyme and as a ligand, has been implicated in cancer progression. The role of CatD in pancreatic ductal adenocarcinoma is unknown.MethodsCatD expression quantified by immunohistochemistry of tumor-tissue microarrays of 403 resected pancreatic cancer patients from the ESPAC-Tplus trial, a translational study within the ESPAC (European Study Group for Pancreatic Cancer) trials, was dichotomously distributed to low and high H scores (cut off 22.35) for survival and multivariable analysis. The validation cohort (n = 69) was recruited based on the hazard ratio of CatD from ESPAC-Tplus. 5-fluorouracil-, and gemcitabine-resistant pancreatic cancer cell lines were employed for mechanistic experiments. All statistical tests were two-sided.ResultsMedian overall survival was 23.75 months and median overall survival for patients with high CatD expression was 21.09 (95% confidence interval [CI] = 17.31 to 24.80) months vs 27.20 (95% CI = 23.75 to 31.90) months for low CatD expression (χ2LR, 1DF = 4.00; P = .04). Multivariable analysis revealed CatD expression as a predictive marker in gemcitabine-treated (z stat = 2.33; P = .02) but not in 5-fluorouracil-treated (z stat = 0.21; P = .82) patients. An independent validation cohort confirmed CatD as a negative predictive marker for survival (χ2LR, 1DF = 6.80; P = .009) and as an independent predictive marker in gemcitabine-treated patients with a hazard ratio of 3.38 (95% CI = 1.36 to 8.38, P = .008). Overexpression of CatD was associated with a concomitant suppression of the acid sphingomyelinase, and silencing of CatD resulted in upregulation of acid sphingomyelinase with rescue of gemcitabine resistance.ConclusionsAdjuvant gemcitabine is less effective in pancreatic ductal adenocarcinoma with high CatD expression, and thus CatD could serve as a marker for biomarker-driven therapy.

Chemotherapy for pancreatic cancer

Chemotherapy is an important part of multimodality pancreatic cancer treatment. After curative resection, adjuvant chemotherapy can significantly improve disease free survival and overall survival. The current standard of care is six months adjuvant chemotherapy with modified folinic acid, 5-fluorouracil, irinotecan and oxaliplatin (mFOLFIRINOX) in patients fit enough for this protocol, otherwise six months of gemcitabine and capecitabine based on the European Study Group for Pancreatic Cancer (ESPAC)-4 study. In patients with metastatic disease, combination chemotherapy according to the FOLFIRINOX protocol or with gemcitabine plus nab-paclitaxel is an important improvement to gemcitabine monotherapy that was the standard for many years. Patients not fit for combination chemotherapy however may still benefit from gemcitabine. Patients with good performance status may benefit from second-line chemotherapy. Chemoradiation has long been used in locally advanced pancreatic cancer but is now tempered following the LAP07 study. This trial showed no difference in overall survival in those patients with stable disease after four months of gemcitabine (with or without erlotinib) randomized to either continuation of gemcitabine therapy or chemoradiation (54Gy with capecitabine). As an alternative to radiation, other forms local therapies including radiofrequency ablation, irreversible electroporation, high-intensity focused ultrasound, microwave ablation and local anti-KRAS therapy (using siG12D-LODER) are currently under investigation. Given the systemic nature of pancreas cancer from an early stage, the success of any local approach other than complete surgical resection (with adjuvant systemic therapy) is likely to be very limited. In patients with locally advanced, irresectable cancer, chemotherapy may offer the chance for secondary resection with a survival similar to patients with primary resectable disease. Downstaging regimens need to be evaluated in prospective randomized trials in order to make firm recommendations. Selection of patient groups for specific therapy including cytotoxics is becoming a reality using assays based on drug cellular transport and metabolism, and molecular signatures. Going forward, high throughput screening of different chemotherapy agents using molecular signatures based on patients' derived organoids holds considerable promise.

Intratumoural expression of deoxycytidylate deaminase or ribonuceotide reductase subunit M1 expression are not related to survival in patients with resected pancreatic cancer given adjuvant chemotherapy

BackgroundDeoxycytidylate deaminase (DCTD) and ribonucleotide reductase subunit M1 (RRM1) are potential prognostic and predictive biomarkers for pyrimidine-based chemotherapy in pancreatic adenocarcinoma.MethodsImmunohistochemical staining of DCTD and RRM1 was performed on tissue microarrays representing tumour samples from 303 patients in European Study Group for Pancreatic Cancer (ESPAC)-randomised adjuvant trials following pancreatic resection, 272 of whom had received gemcitabine or 5-fluorouracil with folinic acid in ESPAC-3(v2), and 31 patients from the combined ESPAC-3(v1) and ESPAC-1 post-operative pure observational groups.ResultsNeither log-rank testing on dichotomised strata or Cox proportional hazard regression showed any relationship of DCTD or RRM1 expression levels to survival overall or by treatment group.ConclusionsExpression of either DCTD or RRM1 was not prognostic or predictive in patients with pancreatic adenocarcinoma who had had post-operative chemotherapy with either gemcitabine or 5-fluorouracil with folinic acid.

Adjuvant Therapy in Pancreatic Cancer

Adjuvant treatment following curative resection for pancreatic cancer is now well established. Historically, the role of adjuvant therapy post resection was uncertain, as was the best form of adjuvant, the choices lying between adjuvant chemotherapy, chemoradiation or a combination of these. The landmark randomized controlled European Study Group for Pancreatic Cancer (ESPAC)-1 trial, provided the strongest evidence for the benefit of adjuvant therapy. ESPAC-1 showed a strong survival advantage for chemotherapy comprising 5-fluorouracil (5-FU) with folinic acid (FA), but no support for the use of chemoradiation. The CONKO-001 trial showed that gemcitabine was also superior to surgery alone. The ESPAC-3 trial showed no superiority for gemcitabine over 5-FU/FA although gemcitabine was less toxic. The effects of adding biological agents or combining agents within regimens are being investigated as well as neo-adjuvant therapies being compared with adjuvant therapy. A network meta-analysis has confirmed reduced survival and increased toxicity with adjuvant chemoradiotherapy. Adjuvant systemic chemotherapy with either gemcitabine or 5-FU/FA following curative resection for pancreatic adenocarcinoma continues as the mainstay of treatment. The five-year survival rates are around 25% with chemotherapy compared to resection alone, with a significant survival benefit also shown for patients with R1 positive resection margins.

The Promise of Modern Radiotherapy in Resected Pancreatic Adenocarcinoma: A Response to Bekaii-Saab et al.

Determining the optimal adjuvant management strategy for patients with resected pancreatic adenocarcinoma remains a controversial topic. In particular, defining the role for radiation continues to generate significant debate. As such, we welcome sustained investigation into whether radiation can improve oncologic outcomes after resection of pancreatic cancer. We therefore appreciate the work done by Bekaii-Saab et al. to review their institution’s experience with adjuvant chemoradiation for localized pancreatic cancer in which they find no benefit on overall survival or local control when comparing patients treated with chemoradiation versus chemotherapy alone. Despite their results, we disagree with the authors’ conclusion that there is ‘‘no benefit from chemoradiation over chemotherapy in the adjuvant treatment of pancreas cancer’’ and that ‘‘based on the available data and outside of a clinical trial, patients should be treated with chemotherapy alone following surgery.’’ Appreciation of the potential that modern radiotherapy may have for resected pancreatic cancer requires a historical understanding of early clinical trials that explored chemoradiation, some of which are referenced by the authors. Early institutional reports demonstrated poor local control after surgical resection of pancreatic cancer, with local failure rates of roughly 50 %. 1 As such, the Gastrointestinal Tumor Study Group (GITSG) undertook a clinical trial comparing 5-fluorouracil (5-FU)-based chemoradiation versus observation in patients undergoing Whipple resection. The chemoradiation arm experienced improved 2-year overall survival (42 vs. 15 %, p = 0.03), leading to widespread adoption of adjuvant chemoradiation in the United States. 2 However, this survival benefit could not be replicated in subsequent trials by the European Organization for Research and Treatment of Cancer (EORTC) and the European Study Group for Pancreatic Cancer (ESPAC), with the latter trial demonstrating the best outcomes in patients treated with chemotherapy alone. 3,4 The

Therapeutic Advances in Pancreatic Cancer

Despite our improved understanding of pancreatic cancer biology and ability to perform more complex pancreatic cancer surgeries that produce better short-term outcomes, major progress toward increasing survival times has been painstakingly slow. Through the often-repeated, dismal survival statistics, it is easy to lose sight of real progress that has been made in pancreatic cancer therapy. It is particularly interesting to observe the extent to which these advances are interdependent and the effects they have had on practice. For example, during the past 5-10 years, we have seen widespread adoption of pancreatic imaging protocols that allow for objectively defined criteria of resectability. This has led to the definition of "borderline resectable pancreatic cancer"--a new clinical category that has affected the design of clinical trials. A major change in our surgical approach has been the move to minimally invasive pancreatectomy, which continues to gain broader acceptance and use, particularly for left-sided lesions. Although many new agents have been developed aimed at putative molecular targets, recent breakthroughs in therapy for advanced disease have arisen from our ability to safely give patients combination cytotoxic chemotherapy. We are now faced with the challenge of combining multidrug, cytotoxic chemotherapies with newer-generation agents. Ultimately, the hope is that drug combinations will be selected based on biomarkers, and strategies for pancreatic cancer therapy will be personalized, which could prolong patients' lives and reduce toxicity. We review the major advances in pancreatic cancer therapy during the last 5 years, and discuss how these have set the stage for greater progress in the near future.

Evolving Panorama of Treatment for Metastatic Pancreas Adenocarcinoma

Evolving Panorama of Treatment for Metastatic Pancreas Adenocarcinoma

Trends in the Use of Postoperative Radiation Therapy in Patients With Localized Resectable Pancreatic Cancer

: Results from European Study Group for Pancreatic Cancer (ESPAC)-1, first published in 2001, suggested that postoperative radiation therapy (PORT) was detrimental in pancreatic patients. The potential association between the publication of ESPAC-1 and the use of PORT in the United States is examined in this study. : Data from the Surveillance, Epidemiology, and End Results program were used to identify pancreatic patients treated with surgical resection followed by PORT. The use of PORT was examined in the 5-year time period preceding and after the publication of ESPAC-1. : Univariable analysis of the use of PORT found significantly less use of PORT in the postpublication period [odds ratio (OR) for the use of PORT in prepublication period=1.19, 95% confidence interval (CI), 1.04-1.35]. A multivariable analysis, performed to account for imbalances in clinical and demographic variables between the 2 time periods, found similar results (OR=1.18, 95% CI, 1.03-1.35). When other types of radiation, such as preoperative radiation were included, no significant difference between time periods was found (OR=0.99, 95% CI, 0.76-1.30). : Although there continues to be frequent use of PORT in the United States, the publication of ESPAC-1 seems to be associated with a small but significant change in its use. However, it is important to note that further analyses suggest that a small shift toward more preoperative radiation may also account for the decrease in PORT.

Adjuvant Chemotherapy for Resected Periampullary Adenocarcinoma

To the Editor: Dr Neoptolemos and colleagues reported results from the large, multicenter European Study Group for Pancreatic Cancer (ESPAC)-3 periampullary randomized controlled trial, which demonstrated no significant overall survival benefit from adjuvant chemotherapy in patients with nonpancreatic periampullary adenocarcinoma. We have 2 comments with regard to the trial data. We believe a central pathological review of the primary sites of origin should have been conducted to provide added clarity and further insight into the study. First, the determination of the primary site of origin (epicenter) of the resected periampullary cancers remains a challenge and is best conducted by a gastrointestinal pathologist. In the European Organization for Research and Treatment of Cancer (EORTC) phase 3 study of adjuvant radiotherapy in patients with pancreatic and periampullary carcinomas, central pathology review changed the diagnosis (pancreatic, periampullary, or unknown) in 5% of the cases. We believe the rate might be higher in this study because central pathology review would be required to solve the additional and more challenging problem of determining the specific sites of nonpancreatic periampullary adenocarcinoma (biliary, duodenal, or ampullary). In the ESPAC-3 study, 2 pancreatic pathologists reviewed each pathology report without reviewing histological slides. This has inherent limitations as demonstrated by the inability to properly classify the histological subtypes (pancreaticobiliary, intestinal, or mixed) of ampullary carcinoma in 162 patients (55%). Second, the low frequency of duodenal adenocarcinoma (2%) in this periampullary cohort contrasts with prior periampullary data sets in which duodenal adenocarcinoma was generally more common and represented 25% to 33% of nonpancreatic periampullary adenocarcinoma cases. We believe this reflects the degree of uncertainty with regard to the ascribed primary sites of periampullary adenocarcinoma. Because the site of nonpancreatic periampullary adenocarcinoma was a significant variable in the multivariate modeling, the uncertainty in determining the primary site of the periampullary adenocarcinoma in this study would limit the interpretation of the secondary multiple regression survival analysis. Could the authors also specify if the initiation of adjuvant therapy was restricted by a maximum time postsurgery and if a restaging imaging study was required prior to initiation of therapy?

Adjuvant Chemotherapy With Fluorouracil Plus Folinic Acid vs Gemcitabine Following Pancreatic Cancer Resection

Adjuvant fluorouracil has been shown to be of benefit for patients with resected pancreatic cancer. Gemcitabine is known to be the most effective agent in advanced disease as well as an effective agent in patients with resected pancreatic cancer. To determine whether fluorouracil or gemcitabine is superior in terms of overall survival as adjuvant treatment following resection of pancreatic cancer. The European Study Group for Pancreatic Cancer (ESPAC)-3 trial, an open-label, phase 3, randomized controlled trial conducted in 159 pancreatic cancer centers in Europe, Australasia, Japan, and Canada. Included in ESPAC-3 version 2 were 1088 patients with pancreatic ductal adenocarcinoma who had undergone cancer resection; patients were randomized between July 2000 and January 2007 and underwent at least 2 years of follow-up. Patients received either fluorouracil plus folinic acid (folinic acid, 20 mg/m(2), intravenous bolus injection, followed by fluorouracil, 425 mg/m(2) intravenous bolus injection given 1-5 days every 28 days) (n = 551) or gemcitabine (1000 mg/m(2) intravenous infusion once a week for 3 of every 4 weeks) (n = 537) for 6 months. Primary outcome measure was overall survival; secondary measures were toxicity, progression-free survival, and quality of life. Final analysis was carried out on an intention-to-treat basis after a median of 34.2 (interquartile range, 27.1-43.4) months' follow-up after 753 deaths (69%). Median survival was 23.0 (95% confidence interval [CI], 21.1-25.0) months for patients treated with fluorouracil plus folinic acid and 23.6 (95% CI, 21.4-26.4) months for those treated with gemcitabine (chi(1)(2) = 0.7; P = .39; hazard ratio, 0.94 [95% CI, 0.81-1.08]). Seventy-seven patients (14%) receiving fluorouracil plus folinic acid had 97 treatment-related serious adverse events, compared with 40 patients (7.5%) receiving gemcitabine, who had 52 events (P < .001). There were no significant differences in either progression-free survival or global quality-of-life scores between the treatment groups. Compared with the use of fluorouracil plus folinic acid, gemcitabine did not result in improved overall survival in patients with completely resected pancreatic cancer. clinicaltrials.gov Identifier: NCT00058201.

Adjuvant EBRT improves survival in patients with lymph-node-negative pancreatic cancer

Therole of adjuvant external-beam radiotherapy (EBRT) for the treatment of pancreatic adenocarcinoma remains controversial.A randomised trial by the Gastrointestinal Study Group demonstrated a survival benefit with the addition of chemoradiotherapy to surgery, and a randomised trial by the European Organisation for Research andTreatment ofCancer also showed a trend towards improved survivalwith adjuvant chemoradiotherapy. On the other hand, a randomised trial by the European Study Group for PancreaticCancer (ESPAC),which comprised four adjuvant treatment arms (observation, chemotherapy alone, radiotherapy with concurrent chemotherapy, and radiotherapy with concurrent chemotherapy followedbymaintenance chemotherapy), revealed that the survival of patientswho received radiotherapy (with or without maintenance chemotherapy) was inferior to that of patients who did not receive radiotherapy. The authors of this report concluded that radiotherapy haddeleterious effects on survival. The reasons for the decrease in survival in patients receiving radiotherapy on the ESPAC trial remain unclear. Radiation was not reported to increase treatment-relatedmortality, but late radiation toxicity is difficult to report accurately because it can be difficult to differentiate from symptoms of a progressive tumour, andpatientsmaybe lost to follow-up. The ESPAC trial did not describe radiation field size and technique, and central review of radiation plans was not required. The Radiation Therapy Oncology Group (RTOG) has reported that amajor deviation from the protocol-defined radiation therapy plan was associated with inferior survival for patientswith pancreatic cancer enrolled on the RTOG 97-04 trial, suggesting that radiation technique is important. The current study based on the SEER registry by Artinyan et al. (see opposite) demonstrates that the addition of radiotherapy to surgery in patients with T1–3N0M0 pancreatic adenocarcinoma is associated with improved survival. Limitations of the SEER registry include its retrospective nature and lack of information regarding surgical-margin status and the use of chemotherapy. In addition, it is not possible to determine any bias in the

Radiochemoimmunotherapy for pancreatic cancer

After they undergo surgical intervention with curative intention in specialized centers, the 5-year survival rate of patients with carcinoma of the exocrine pancreas is only 15%. The European Study Group For Pancreatic Cancer (ESPAC) –1 trial showed that an increased 5-year survival rate of 21% was achieved with adjuvant chemotherapy. Investigators from the Virginia Mason Clinic have reported a 5-year survival rate of 55% in a phase II trial evaluating adjuvant chemotherapy, immunotherapy, and external-beam radiation. This article discusses the potential role of radiochemoimmunotherapy for adjuvant treatment; describes the ongoing phase III randomized controlled trial, Adjuvant ChemoRadioImmunotherapy of Pancreatic Carcinoma (CapRI); and compares the regimen from the Virginia Mason Clinic with the best arm of ESPAC-1. First data regarding the toxicity are shown. This article illustrates possible modes of action of radiochemoimmunotherapy and shows how translational research might help to shed some light on the underlying mechanisms as well as define predictive markers.

Adjuvant chemotherapy—the standard after resection for pancreatic cancer

Pancreatic cancer is one of the major causes of cancer death. Most patients present with advanced disease, and only 10% to 15% can undergo resection. Survival after curative surgery is poor, as recurrences occur either locally or in the liver. Adjuvant treatment has been employed to improve the poor prognosis. There is a clear-cut survival advantage with 5-fluorouracil (5-FU)/folinic acid or gemcitabine compared with observation, based on the results from the European Study Group for Pancreatic Cancer (ESPAC) 1 and Neuhaus studies. The survival advantage associated with chemotherapy is supported by an individual patient data meta-analysis. In contrast, there is no justification for the use of adjuvant chemoradiation based on the European Organization for Research and Treatment of Cancer (EORTC) and ESPAC-1 trial results. The use of chemoradiation followed by chemotherapy, as shown in the 1987 Gastrointestinal Tumor Study Group (GITSG) study and the recent Radiation Therapy Oncology Group (RTOG) 9704 combination study, has not proved to be superior to chemotherapy alone based on the results of the underpowered study. The standard of care for adjuvant therapy based on level I evidence is postoperative chemotherapy using 5-FU with folinic acid, providing a best estimate of 29% 5-year survival rate.

Future Chemoradiation Strategies in Pancreatic Cancer

Although not universally accepted, 5-fluorouracil (5-FU)-based chemoradiation is considered a standard treatment for patients with localized pancreatic cancer. Randomized trials have indicated that chemoradiation improves median survival of both locally advanced and resected pancreatic cancer. While the use of adjuvant chemoradiation in pancreatic cancer has been called into question since the publication of the European Study Group for Pancreatic Cancer (ESPAC)-1 trial, this study has not changed standard practice in the United States. All randomized trials investigating adjuvant chemoradiation have reported significant local as well as distant disease control limitations, making the study of novel chemoradiation and adjuvant chemotherapy important. Selected centers are investigating neoadjuvant chemoradiation in radiographically resectable patients. Advantages of neoadjuvant chemoradiation compared to postoperative therapy include increased local control, increased access to therapy, addressing the systemic disease recurrence risk without delay, and optimal patient selection for pancreaticoduodenectomy through exclusion of patients with rapidly progressive metastatic disease. In the years since it was approved for use in pancreatic cancer, gemcitabine has stood the test of time as a systemic agent but has not been widely adopted as a radiosensitzer in pancreatic cancer. Single-arm clinical trials that initially explored gemcitabine as a radiosensitzer in locally advanced pancreatic cancer demonstrated the potential for significant toxicity without dramatic improvements in efficacy. Recent strategies for improving the efficacy of chemoradiation include improved chemoradiation sensitization through the concurrent incorporation of molecular targeted agents, and the use of new radiation technology such as intensity-modulated radiotherapy (IMRT) and stereotactic radiotherapy. Herein, we discuss the relative merits of strategies that seek to improve outcome through these novel means and present recent data from novel strategies that will provide the background for future trials.

Adjuvant Therapy in Pancreatic Cancer

Adenocarcinoma of the pancreas carries a grim prognosis. Surgery is currently the only curative option, but even the few patients undergoing complete resection of early localised disease run a high risk for relapse and death. Although numerous clinical trials have been conducted during the past 20 years to find an effective adjuvant treatment, thus far no general consensus on the most appropriate regimen has been reached. In a small randomised study performed in the 1980s by the GITSG (Gastrointestinal Tumor Study Group), encouraging results were obtained with fluorouracil (5-FU)-based split-course chemoradiotherapy, but these findings were not confirmed in a randomised study initiated some years later by the EORTC (European Organisation for Research and Treatment of Cancer). More recently, the ESPAC (European Study Group for Pancreatic Cancer)-1 trial even indicated a detrimental effect of chemoradiotherapy, while chemotherapy with 5-FU was shown to have a significant positive impact on long-term survival. However, this latter finding is in contrast to earlier studies of adjuvant chemotherapy with 5-FU combinations from Norway and Japan that did not suggest a prolonged beneficial effect of 5-FU on survival. Thus, the results for adjuvant regimens based on systemic 5-FU with or without external radiotherapy are conflicting. Clinical experience with intraoperative radiotherapy or regionally targeted chemotherapy to prevent local relapse, though encouraging, is still preliminary. More recently, gemcitabine, which is the most effective single agent in advanced pancreatic cancer, has also been evaluated in the adjuvant setting. The RTOG (Radiation Therapy Oncology Group)-9704 trial demonstrated that gemcitabine is superior to 5-FU as an addition to chemoradiotherapy, but the results did not allow conclusions about the value of radiation in the combined modality approach. The Charité Onkologie CONKO-001 is a randomised trial from Germany and Austria that compared adjuvant gemcitabine with observation alone. Gemcitabine was very well tolerated and almost doubled median disease-free survival and overall survival rate at 5 years, although the advantage in overall survival failed to reach statistical significance. In summary, the available data from randomised clinical trials of adjuvant therapy suggest that (i) chemoradiotherapy has no obvious advantage compared with chemotherapy alone; and (ii) chemotherapy with gemcitabine is effective and probably offers the best benefit-risk ratio of all currently available adjuvant treatment options.

Adjuvant therapy in pancreatic cancer: historical and current perspectives

The results from pancreatic ductal adenocarcinoma appear to be improving with increased resection rates and reduced postoperative mortality reported by specialist pancreatic cancer teams. Developments with medical oncological treatments have been difficult, however, due to the fundamentally aggressive biological nature of pancreatic cancer and its resistance to chemotherapy coupled with a relative dearth of randomised controlled trials. The European Study Group for Pancreatic Cancer (ESPAC)-1 trial recruited nearly 600 patients and is the largest trial in pancreatic cancer. The results demonstrated that the current best adjuvant treatment is chemotherapy using bolus 5-fluorouracil with folinic acid. The median survival of patients randomly assigned to chemoradiotherapy was 15.5 months and is comparable with many other studies, but the median survival in the chemotherapy arm was 19.7 months and is as good or superior to multimodality treatments including intra-operative radiotherapy, adjuvant chemoradiotherapy and neo-adjuvant therapies. The use of adjuvant 5-fluorouracil with folinic acid may be supplanted by gemcitabine but requires confirmation by ongoing clinical trials, notably ESPAC-3, which plans to recruit 990 patients from Europe, Canada and Australasia. Major trials such as ESPAC-1 and ESPAC-3 have set new standards for the development of adjuvant treatment and it is now clear that such treatment in this field has the potential to significantly improve both patient survival and quality of life after curative resection.

Adjuvant therapy in operable pancreatic cancer.

Adenocarcinoma of the pancreas remains a highly lethal disease with one of the worst mean survival rates of all solid malignancies. Even with improvements in surgical techniques in the last decades, the five-year survival rate of patients following resection is still under 20 percent. Various additional treatment concepts have been introduced based on encouraging results for adjuvant chemoradiotherapy obtained in a small randomized-controlled trial more than 15 years ago. The purpose of this article is to review the results of several trials investigating adjuvant therapy for pancreatic cancer. We will discuss recent studies of EORTC (European Organization for Research and Treatment of Cancer), ESPAC (European Study Group for Pancreatic Cancer) and others and will also focus on future alternative treatment options for pancreatic cancer.

Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial

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 randomised study. After resection, patients were randomly 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 randomise 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 randomised: 285 in the two-by-two factorial design (70 chemoradiotherapy, 74 chemotherapy, 72 both, 69 observation); a further 68 patients were randomly 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 randomised controlled trials of adjuvant chemotherapy in pancreatic cancer.