Neoadjuvant Treatment in Resectable Pancreatic Cancer

NCT ID: NCT01900327

Last Updated: 2018-05-11

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 32 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-02-28
• Study Completion Date: 2017-07-31

Brief Summary

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

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.

Conditions

Pancreatic Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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).

Group Type: EXPERIMENTAL

External Beam Radiation

Intervention Type: RADIATION

Neoadjuvant CRT with external beam radiation (EBRT) delivering a total dose of 50.4 Gy over 28 days in 1.8 Gy fractions.

Gemcitabine neoadjuvant

Intervention Type: DRUG

weekly Gemcitabine 300mg/m2 for 6 weeks neoadjuvant

Surgery

Intervention Type: PROCEDURE

Upfront pancreato-duodenectomy

Gemcitabine adjuvant

Intervention Type: DRUG

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

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).

Group Type: ACTIVE_COMPARATOR

Surgery

Intervention Type: PROCEDURE

Upfront pancreato-duodenectomy

Gemcitabine adjuvant

Intervention Type: DRUG

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

Interventions

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.

Intervention Type: RADIATION

Gemcitabine neoadjuvant

weekly Gemcitabine 300mg/m2 for 6 weeks neoadjuvant

Intervention Type: DRUG

Surgery

Upfront pancreato-duodenectomy

Intervention Type: PROCEDURE

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

Intervention Type: DRUG

Other Intervention Names

External Beam Radiation Therapy; EBRT; Gemcitabin; Gemzar; Tumor resection; Gemcitabin; Gemzar; 2',2'-Difluordesoxycytidin

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University Hospital Schleswig-Holstein

OTHER

Sponsor Role: collaborator

Hannover Medical School

OTHER

Sponsor Role: collaborator

St. Josef Hospital Bochum

OTHER

Sponsor Role: collaborator

University of Jena

OTHER

Sponsor Role: collaborator

SRH Wald-Klinikum Gera GmbH

OTHER

Sponsor Role: collaborator

Klinikum Darmstadt

OTHER

Sponsor Role: collaborator

Universität des Saarlandes

OTHER

Sponsor Role: collaborator

Heidelberg University

OTHER

Sponsor Role: collaborator

Staedtisches Klinikum Karlsruhe

OTHER

Sponsor Role: collaborator

University Hospital Freiburg

OTHER

Sponsor Role: collaborator

University Hospital Regensburg

OTHER

Sponsor Role: collaborator

Technical University of Munich

OTHER

Sponsor Role: collaborator

University Hospital Augsburg

OTHER

Sponsor Role: collaborator

Klinikum Stuttgart

OTHER

Sponsor Role: collaborator

Ludwig-Maximilians - University of Munich

OTHER

Sponsor Role: collaborator

University of Rostock

OTHER

Sponsor Role: collaborator

Universitätsklinikum Hamburg-Eppendorf

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jakob R Izbicki, MD, FACS

Role: PRINCIPAL_INVESTIGATOR

Universitätsklinikum Hamburg-Eppendorf

Locations

University Freiburg

Freiburg im Breisgau, Baden-Wurttemberg, Germany

Heidelberg University

Heidelberg, Baden-Wurttemberg, Germany

Technische Universität München

München, Bavaria, Germany

University Regensburg

Regensburg, Bavaria, Germany

Klinikum Augsburg

Augsburg, Bayer, Germany

Klinikum Darmstadt

Darmstadt, Hesse, Germany

Hannover Medical School

Hanover, Lower Saxony, Germany

University of Rostock

Rostock, Mecklenburg-Vorpommern, Germany

St. Joseph Hospital Bochum

Bochum, North Rhine-Westphalia, Germany

Saarland University

Homburg, Saarland, Germany

University of Schleswig-Holstein Kiel

Kiel, Schleswig-Holstein, Germany

University of Schleswig-Holstein Lübeck

Lübeck, Schleswig-Holstein, Germany

Klinikum Gera

Gera, Thuringia, Germany

University of Jena

Jena, Thuringia, Germany

University Medical Center Hamburg-Eppendorf

Hamburg, , Germany

Klinikum Karlsruhe

Karlsruhe, , Germany

Countries

Germany

References

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.

Reference Type: DERIVED

PMID: 24906700 (View on PubMed)

Related Links

http://www.uke.de

Homepage University Medical Center

Other Identifiers

NEOPA

Identifier Type: -

Identifier Source: org_study_id