Neoadjuvant Treatment in Resectable Pancreatic Cancer (NEOPA)

Sequential Neoadjuvant Chemoradiotherapy (CRT) Followed by Curative Surgery vs. Primary Surgery Alone for Resectable, Non-metastasized Pancreatic Adenocarcinoma

Sequential Neoadjuvant Chemoradiotherapy (CRT) Followed by Curative Surgery vs. Primary Surgery Alone for Resectable, Non-metastasized Pancreatic Adenocarcinoma

Study Overview

• Status: Terminated
• Conditions: Pancreatic Cancer
• Intervention / Treatment: Radiation: External Beam Radiation; Drug: Gemcitabine neoadjuvant; Procedure: Surgery; Drug: Gemcitabine adjuvant

Detailed Description

Median overall-survival (OS) after surgery in curative intent for non-metastasized pancreas cancer ranges under study conditions from 17.9 months to 23.6 months. Tumor recurrence occurs locally, at distant sites (liver, peritoneum, lungs), or both. Observational and autopsy series report local recurrence rates of up to 87% even after potentially "curative" R0 resection. To achieve better local control, neoadjuvant chemo-radiation therapy (CRT) has been suggested for preoperative tumour downsizing, to elevate the likelihood of curative, margin-negative R0 resection and to increase the OS rate. However, controlled, randomized trials addressing the impact of neoadjuvant CRT survival do not exist. The underlying hypothesis of this randomized, two-armed, open-label, multicenter, phase III trial is that neoadjuvant CRT increases the three-year overall survival by 12% (30% to 42%) compared to patients undergoing upfront surgery for resectable pancreatic cancer. Overall, 410 patients (n=205 in each study arm) will be enrolled in the trial, taking into regard an expected drop out rate of 7% and allocated either to receive neoadjuvant CRT prior to surgery or to undergo surgery alone. Circumferential resection margin status, i.e. R0 and R1 rates, respectively, surgical resectability rate, local and distant disease-free and global survival, and first site of tumor recurrence constitute further essential endpoints of the trial.

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Hamburg, Germany, 20246
    • University Medical Center Hamburg-Eppendorf
  • Karlsruhe, Germany, 76133
    • Klinikum Karlsruhe
  • Baden-Württemberg
    • Freiburg, Baden-Württemberg, Germany, 79106
      • University Freiburg
    • Heidelberg, Baden-Württemberg, Germany, 69120
      • Heidelberg University
  • Bayer
    • Augsburg, Bayer, Germany, 86156
      • Klinikum Augsburg
  • Bayern
    • München, Bayern, Germany, 81675
      • Technische Universität München
    • Regensburg, Bayern, Germany, 93053
      • University Regensburg
  • Hessen
    • Darmstadt, Hessen, Germany, 64283
      • Klinikum Darmstadt
  • Mecklenburg-Vorpommern
    • Rostock, Mecklenburg-Vorpommern, Germany, 18057
      • University of Rostock
  • Niedersachsen
    • Hannover, Niedersachsen, Germany, 30625
      • Hannover Medical School
  • Nordrhein-Westfalen
    • Bochum, Nordrhein-Westfalen, Germany, 44791
      • St. Joseph Hospital Bochum
  • Saarland
    • Homburg, Saarland, Germany, 66421
      • Saarland University
  • Schleswig-Holstein
    • Kiel, Schleswig-Holstein, Germany, 24105
      • University of Schleswig-Holstein Kiel
    • Lübeck, Schleswig-Holstein, Germany, 23538
      • University of Schleswig-Holstein Lübeck
  • Thüringen
    • Gera, Thüringen, Germany, 07548
      • Klinikum Gera
    • Jena, Thüringen, Germany, 07747
      • University of Jena

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histology-proven adenocarcinoma of the pancreatic head/uncinate process with a tumor size greater 2 cm (≥cT2) and/or close contact to the superior mesenteric vessels (≤3 mm in preoperative staging).
• No evidence of metastasis to distant organs (liver, peritoneum, lung, others).
• For determination of resectability, a multi-detector CT (MDCT) with at least 16 rows applying both oral and intravenous contrast media is performed. MDCT-based imaging focuses on the upper abdomen with native, arterial, and parenchyma phase, where the parenchyma phase should include the pelvis. Imaging criteria derived from the recent consensus definition of the Society of Surgical Oncology, the American Society of Clinical Oncology and the American Hepato-Pancreatico-Biliary Association [1] are applied for preoperative assessment of local resectability.
• Potential Resectability: visualizable fat plane around celiac and superior mesenteric arteries, and patent superior mesenteric/portal vein (SMV/PV).
• Borderline Resectability: substantial superior mesenteric/portal vein impingement, tumor abutment on the SMA < 180°, GDA encasement up to the origin of the hepatic artery, or colonic/mesenteric root invasion.
• Karnofsky performance status ≥ 80%
• Serum creatinine level ≤ 3.0 mg/dl
• Serum total bilirubin level ≤ 3.0 mg/dl in the absence of biliary obstruction (In the event of biliary obstruction, patients allocated to the CRT group must undergo interventional endoscopy or percutaneous drainage for biliary decompression. Post-interventionally, bilirubin levels should be ≤ 3.0 mg/dl before patients are subjected to CRT. In control patients undergoing upfront surgery, serum total bilirubin levels ≤ 10.0 mg/dl are tolerated, unless clinical and laboratory signs of severe cholangitis take place. Patients with serum total bilirubin level > 10.0 mg/dl undergo preoperative biliary decompression, preferentially by interventional endoscopy)
• White blood cell count ≥ 3.5 x 109/ml, platelet count ≥ 100 x 109/ml
• Ability to understand and willingness to consent to formal requirements for study participation
• Written informed consent

Exclusion Criteria:

• Age ≤ 18 years
• Neuroendocrine, acinar cancer
• Cancers of the pancreatic body or tail, i.e. lesions left to the SMV
• Recurrent disease
• Infiltration of extrapancreatic organs (except duodenum and transverse colon)
• Persistent cholestasis/cholangitis despite adequate biliary stenting
• Gastric outlet obstruction, especially in the event of endoscopically evidenced tumor invasion into the gastroduodenal mucosa.
• Tumor specific pre-treatment
• History of gastrointestinal perforation, e.g. perforated colonic diverticulitis, abdominal abscess or intestinal fistula within 6 months prior to potential study participation
• Radiographic evidence of severe portal hypertension/cavernomatous transformation that may, at the discretion of the participating investigators, hamper surgery
• Other concurrent malignancies except for basal cell cancer of the skin and in-situ cervical cancer
• Premalignant hematologic disorders, e.g. myelodysplastic syndrome
• Severe organ dysfunctions (e.g. Liver cirrhosis ≥ Child B; Cardio-pulmonal diseases (NYHA ≥III, arrhythmia Lown III/IV, global respiratory insufficiency); Ascites; Acute pancreatitis; bleeding diathesis, coagulopathy, need for full-dose anticoagulation or INR > 1.5; other severe diseases that might prevent completion of the treatment regimen)
• Chronic infectious diseases, especially immune deficiency syndromes, e.g. HIV infection, active tuberculosis within 12 months prior to potential study participation
• History of severe neurologic disorders, e.g. cerebrovascular ischemia
• History of prior deep venous thrombosis or pulmonary embolism
• Pregnant or nursing women are ineligible and patients of reproductive potential must agree to use an effective contraceptive method during participation in this trial and for 6 months following the trial
• Serious medical, psychological, familial, sociological or geographical conditions or circumstances potentially hampering compliance with the study protocol and follow-up Participation in other clinical trials during the last 6 months before allocation to trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: neoadj. Treatment; Neoadjuvant CRT with weekly Gemcitabine neoadjuvant 300mg/m2 for 6 weeks combined with external beam radiation (EBRT) delivering a total dose of 50.4 Gy over 28 days in 1.8 Gy fractions will be followed by classical or pylorus-preserving partial pancreato-duodenectomy (PD) and adjuvant chemotherapy (CTx), preferentially using Gemcitabine adjuvant (1000 mg/m2 6 cycles at day 1, 8, 15 of each 28-day cycle).	Radiation: External Beam Radiation; Neoadjuvant CRT with external beam radiation (EBRT) delivering a total dose of 50.4 Gy over 28 days in 1.8 Gy fractions.; Other Names: EBRT; External Beam Radiation Therapy; Drug: Gemcitabine neoadjuvant; weekly Gemcitabine 300mg/m2 for 6 weeks neoadjuvant; Other Names: Gemzar; Gemcitabin; Procedure: Surgery; Upfront pancreato-duodenectomy; Other Names: Tumor resection; Drug: Gemcitabine adjuvant; Postoperative adjuvant Chemotherapy preferentially using Gemcitabine (1000 mg/m2 6 cycles at day 1, 8, 15 of each 28-day cycle. Administered in both arms, experimental AND active comparator; Other Names: Gemzar; Gemcitabin; 2',2'-Difluordesoxycytidin
Active Comparator: Upfront Surgery; Upfront PD followed by adjuvant CTx, preferentially with Gemcitabine adjuvant (1000 mg/m2 6 cycles at day 1, 8, 15 of each 28-day cycle).	Procedure: Surgery; Upfront pancreato-duodenectomy; Other Names: Tumor resection; Drug: Gemcitabine adjuvant; Postoperative adjuvant Chemotherapy preferentially using Gemcitabine (1000 mg/m2 6 cycles at day 1, 8, 15 of each 28-day cycle. Administered in both arms, experimental AND active comparator; Other Names: Gemzar; Gemcitabin; 2',2'-Difluordesoxycytidin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
3-Year Survival Rate	Primary outcome measure is the efficacy of neoadjuvant CRT in improving 3-year survival probability from 30% in the control arm undergoing upfront surgery without neoadjuvant CRT to 42% (relative increase of 40%) in the study arm undergoing CRT. The underlying guess of a 30% 3-year survival probability in the control group derives from an assumed median overall survival (MOS) of 20.7 months which corresponds with a MOS of 17.9 months to 23.6 months reported in several randomized trials.	3 years after last patient in

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
R0 Resection rate	Histology-proven R0 resection rate based on a standardized histopathological handling of the surgical specimen.	3 days
Frequency of Toxicity Events	Frequency of moderate and severe toxicity events and drop-out rate due to therapy related toxicity (NCI Common Toxicity Criteria v2.0)	three years
Resectability rate	Resectability rate	one day
Rate of intraoperative irregularities	Rate of unexpected intraoperative irregularities, operative time, blood transfusion requirement, postoperative morbidity rate, especially that of pancreatic fistula, and mortality rate	one day
Postoperative Complications	Rate of patients with severe postoperative complications (postoperative recovery > 8 weeks) rendering adjuvant treatment worthless	three months
Disease progression during neoadjuvant therapy	Rate of patients with disease progression during neoadjuvant therapy (only applicable in treatment arm)	three months
Quality of life	Quality of life analysis (EORTC QLQ C30 questionnaire). Assessment of QLQ after completion of neoadjuvant RCTx, after surgery (before hospital discharge) and 6, 12 and 18 months after completion of treatment	three years
Disease-free Survival	Median disease-free survival (DFS, local and distant), overall survival (OS)	three years
First site of tumor recurrence	First site of tumor recurrence as determined by abdominal computed tomography during follow-up study visits	two years

Collaborators and Investigators

• Sponsor: Universitätsklinikum Hamburg-Eppendorf
• Collaborators: Hannover Medical School; Ludwig-Maximilians - University of Munich; Heidelberg University; University of Jena; Technical University of Munich; University Hospital Schleswig-Holstein; University Hospital Freiburg; Universität des Saarlandes; University of Rostock; University Hospital Regensburg; St. Josef Hospital Bochum; SRH Wald-Klinikum Gera GmbH; Klinikum Darmstadt; Staedtisches Klinikum Karlsruhe; University Hospital Augsburg; Klinikum Stuttgart
• Investigators: Principal Investigator: Jakob R Izbicki, MD, FACS, Universitatsklinikum Hamburg-Eppendorf

Publications and helpful links

General Publications

• Tachezy M, Gebauer F, Petersen C, Arnold D, Trepel M, Wegscheider K, Schafhausen P, Bockhorn M, Izbicki JR, Yekebas E. Sequential neoadjuvant chemoradiotherapy (CRT) followed by curative surgery vs. primary surgery alone for resectable, non-metastasized pancreatic adenocarcinoma: NEOPA- a randomized multicenter phase III study (NCT01900327, DRKS00003893, ISRCTN82191749). BMC Cancer. 2014 Jun 7;14:411. doi: 10.1186/1471-2407-14-411.

Helpful Links

• Homepage University Medical Center

Study record dates

Study Major Dates

• Study Start: February 1, 2014
• Primary Completion (Actual): November 22, 2016
• Study Completion (Actual): July 1, 2017

Study Registration Dates

• First Submitted: June 27, 2013
• First Submitted That Met QC Criteria: July 11, 2013
• First Posted (Estimate): July 16, 2013

Study Record Updates

• Last Update Posted (Actual): May 11, 2018
• Last Update Submitted That Met QC Criteria: May 4, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Keywords: surgery; neoadjuvant treatment; pancreatic cancer; chemoradiation; overall survival
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Pancreatic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Gemcitabine
• Other Study ID Numbers: NEOPA