Neoadjuvant Treatment In Resectable Pancreatic Cancer

Study Overview

Neoadjuvant Treatment in Resectable Pancreatic Cancer

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

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 Ȭurative" 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.

Pancreatic Cancer

RADIATION: External Beam Radiation
DRUG: Gemcitabine neoadjuvant
PROCEDURE: Surgery
DRUG: Gemcitabine adjuvant

NEOPA

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2013-06-27	Results First Submitted N/A	Last Update Submitted that met QC Criteria 2018-05-04
First Submitted that Met QC Criteria 2013-07-11	Results First Submitted that Met QC Criteria N/A	Last Update Posted (ACTUAL) 2018-05-11
First Posted (ACTUAL) 2013-07-16	Results First Posted N/A	Last Verified 2018-05

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Randomized

Interventional Model:
Parallel

Masking:
None

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	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. DRUG: Gemcitabine neoadjuvant weekly Gemcitabine 300mg/m2 for 6 weeks neoadjuvant PROCEDURE: Surgery Upfront pancreato-duodenectomy 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
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 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

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

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.

DRUG: Gemcitabine neoadjuvant

weekly Gemcitabine 300mg/m2 for 6 weeks neoadjuvant

PROCEDURE: Surgery

Upfront pancreato-duodenectomy

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

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

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

Primary Outcome Measures	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	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

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

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

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

University Hospital Schleswig-Holstein
Hannover Medical School
St. Josef Hospital Bochum
University of Jena
SRH Wald-Klinikum Gera GmbH
Klinikum Darmstadt
Universität des Saarlandes
Heidelberg University
Staedtisches Klinikum Karlsruhe
University Hospital Freiburg
University Hospital Regensburg
Technical University of Munich
University Hospital Augsburg
Klinikum Stuttgart
Ludwig-Maximilians - University of Munich
University of Rostock

Investigators

PRINCIPAL_INVESTIGATOR: Jakob R Izbicki, MD, FACS, Universitätsklinikum Hamburg-Eppendorf

Publications

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

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.

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