ESPAC-1 Trial Progress Report: The European Randomized Adjuvant Study Comparing Radiochemotherapy, 6 Months Chemotherapy and Combination Therapy versus Observation in Pancreatic Cancer

Neoptolemos, J. P.; Kerr, David; Beger, H G; Link, K. H.; Pederzoli, Paolo; Bassi, Claudio; Dervenis, Christos; Fernández‐Cruz, Laureano; Lacaine, F; Friess, Helmut; Büchler, Markus W.

doi:10.1159/000201503

Cited by 42 publications

(29 citation statements)

References 18 publications

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“…Early prospective adjuvant studies concentrated on patients with negative resection margins (R0), 16 -18 but more recent trials have included patients with margin-positive (R1) resections. 19,23,25,26 The European Study Group for Pancreatic Cancer's first trial (ESPAC-1) was a pragmatic study designed to assess the roles of adjuvant chemoradiation and chemotherapy; patients were stratified prospectively by resection margin status before randomization. 25,26 Hence, the trial was ideal for identifying prognostic factors for patients after resection of pancreatic ductal adenocarcinoma and exploring how resection margin status influenced outcome.…”

Section: Discussionmentioning

confidence: 99%

“…25,26 Unlike previous smaller adjuvant trials that restricted recruitment to patients with negative resection margins, 16 -18 the ESPAC-1 trial allowed all patients to enter the study, stratifying treatment allocation by resection margin status. It was anticipated that 20% of patients would have positive resection margins, and this was found to be the case.…”

Section: Discussionmentioning

confidence: 99%

“…25,26 Most patients underwent a standard pancreatoduodenectomy resection, 30,31 either a classical Kausch-Whipple procedure (52%) or pylorus-preserving pancreatoduodenectomy (36%). The remainder (12%) underwent a standard left or total pancreatectomy 31 for tumors in the tail of the pancreas or large tumors in the body of the gland, respectively.…”

Section: Patientsmentioning

confidence: 99%

“…The study aimed to randomize 280 patients for two treatments in a 2 ϫ 2 factorial design to examine two issues: the role of adjuvant chemoradiation (40 Gy ϩ 5-fluorouracil [5-FU] over 6 weeks, including a 2-week break) and the role for adjuvant chemotherapy (5-FU ϩ folinic acid, 1 week in every 4 weeks for 6 months). 25,26 Although clinicians were encouraged to randomize into this 2 ϫ 2 design, randomization was restricted, and so the trial design was expanded to be more pragmatic and to include single-arm randomization options for chemoradiation only and chemotherapy only (Fig. 1).…”

Section: Treatment Allocationmentioning

confidence: 99%

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Influence of Resection Margins on Survival for Patients With Pancreatic Cancer Treated by Adjuvant Chemoradiation and/or Chemotherapy in the ESPAC-1 Randomized Controlled Trial

Neoptolemos¹,

Stocken²,

Dunn³

et al. 2001

Annals of Surgery

583

344

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ObjectiveTo assess the influence of resection margins on survival for patients with resected pancreatic cancer treated within the context of the adjuvant European Study Group for Pancreatic Cancer-1 (ESPAC-1) study. Summary Background DataPancreatic cancer is associated with a poor long-term survival rate of only 10% to 15% after resection. Patients with positive microscopic resection margins (R1) have a worse survival, but it is not known how they fare in adjuvant studies. MethodsESPAC-1, the largest randomized adjuvant study of resectable pancreatic cancer ever performed, set out to look at the roles of chemoradiation and chemotherapy. Randomization was stratified prospectively by resection margin status. ResultsOf 541 patients with a median follow-up of 10 months, 101 (19%) had R1 resections. Resection margin status was confirmed as an influential prognostic factor, with a median survival of 10.9 months for R1 versus 16.9 months months for patients with R0 margins. Resection margin status remained an independent factor in a Cox proportional hazards model only in the absence of tumor grade and nodal status. There was a survival benefit for chemotherapy but not chemoradiation, irrespective of R0/R1 status. The median survival was 19.7 months with chemotherapy versus 14.0 months without. For patients with R0 margins, chemotherapy produced longer survival compared with to no chemotherapy. This difference was less apparent for the smaller subgroup of R1 patients, but there was no significant heterogeneity between the R0 and R1 groups. ConclusionsResection margin-positive pancreatic tumors represent a biologically more aggressive cancer; these patients benefit from resection and adjuvant chemotherapy but not chemoradiation. The magnitude of benefit for chemotherapy treatment is reduced for patients with R1 margins versus those with R0 margins. Patients with R1 tumors should be included in future trials of adjuvant treatments and randomization and analysis should be stratified by this significant prognostic factor.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Patientsmentioning

confidence: 99%

Section: Treatment Allocationmentioning

confidence: 99%

See 2 more Smart Citations

Influence of Resection Margins on Survival for Patients With Pancreatic Cancer Treated by Adjuvant Chemoradiation and/or Chemotherapy in the ESPAC-1 Randomized Controlled Trial

Neoptolemos¹,

Stocken²,

Dunn³

et al. 2001

Annals of Surgery

583

344

View full text Add to dashboard Cite

show abstract

“…Currently available chemotherapy regimens are undergoing assessment in the adjuvant setting but are not consistently effective in those patients with advanced disease. 4 Novel methods of treatment, which take advantage of molecular mechanisms in cancer, are needed to improve the overall outlook for these patients. The tumour suppressor genes p53 and p16 are frequently mutated with loss of function in pancreatic cancer.…”

Section: Introductionmentioning

confidence: 99%

Adenovirus-mediated transfer of p53 and p16INK4a results in pancreatic cancer regression in vitro and in vivo

et al. 2001

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Pancreatic cancer has a very poor prognosis. Current chemotherapy and radiotherapy regimens are only moderately successful. The tumour suppressor genes p53 and p16INK4a encode cell cycle regulatory proteins that are important candidates for gene replacement therapy. Over 80% of pancreatic adenocarcinoma cases lack detectable p16 protein while over 60% contain mutated p53 protein. We used replication-deficient recombinant adenoviruses to reintroduce wild-type p16 and p53 into pancreatic cancer cells in vitro and into subcutaneous pancreatic tumours in an animal model to determine the effect on tumour growth. Significant growth inhibition was observed in all five human pancreatic cell lines with these viruses (P Ͻ 0.002) compared with simi-

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K-ras oncogene subtype mutations are associated with survival but not expression of p53, p16INK4A, p21WAF-1, cyclin D1, erbB-2 and erbB-3 in resected pancreatic ductal adenocarcinoma

et al. 2000

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Previous studies of molecular prognostic markers following resection for exocrine pancreatic cancer have produced conflicting results. Our aim was to undertake a comprehensive analysis of potentially useful molecular markers in a large, multicentre patient population and to compare these markers with standard pathological prognostic variables. Formalin‐fixed, paraffin‐embedded specimens of pancreatic ductal adenocarcinoma were analysed from 157 patients [100 men and 57 women with a median (range) age of 60 (33–77) years] who had undergone pancreatectomy. Immunohistochemistry was used to detect expression of p16INK4, p53, p21WAF1, cyclin D1, erbB‐2 and erbB‐3. Mutations in codons 12 and 13 of the K‐ras oncogene were detected by SSCP and sequencing following DNA extraction and amplification by PCR. The median (range) survival post‐resection was 12.5 (3–83) months. Abnormalities of p16INK4, p53, p21WAF1, cyclin D1, erbB‐2 and erbB‐3 expression were found in 87%, 41%, 75%, 72%, 33% and 57% of cases, respectively. There was no significant correlation between expression of any of these markers and patient survival. K‐ras mutations were found in 73 (75%) of 97 cases with amplifiable DNA. The presence of K‐ras mutation alone did not correlate with survival, but there were significant differences in survival according to the type of K‐ras mutation (p = 0.0007). Reduced survival was found in patients with GaT, cGT and GcT K‐ras mutations compared to GtT, aGT and GaC mutations. In conclusion, survival was associated with type of K‐ras mutation but not expression of p16INK4, p53, p21WAF1, cyclin D1, erbB‐2 and erbB‐3. Int. J. Cancer 89:469–474, 2000. © 2000 Wiley‐Liss, Inc.

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ESPAC-1 Trial Progress Report: The European Randomized Adjuvant Study Comparing Radiochemotherapy, 6 Months Chemotherapy and Combination Therapy versus Observation in Pancreatic Cancer

Cited by 42 publications

References 18 publications

Influence of Resection Margins on Survival for Patients With Pancreatic Cancer Treated by Adjuvant Chemoradiation and/or Chemotherapy in the ESPAC-1 Randomized Controlled Trial

Influence of Resection Margins on Survival for Patients With Pancreatic Cancer Treated by Adjuvant Chemoradiation and/or Chemotherapy in the ESPAC-1 Randomized Controlled Trial

Adenovirus-mediated transfer of p53 and p16INK4a results in pancreatic cancer regression in vitro and in vivo

K-ras oncogene subtype mutations are associated with survival but not expression of p53, p16INK4A, p21WAF-1, cyclin D1, erbB-2 and erbB-3 in resected pancreatic ductal adenocarcinoma

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