Neoadjuvant Treatment in Resectable Pancreatic Cancer

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

Detailed Description
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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.

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

Conditions
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Pancreatic Cancer

Intervention / Treatment
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* Radiation: External Beam Radiation
* Drug: Gemcitabine neoadjuvant
* Procedure: Surgery
* Drug: Gemcitabine adjuvant


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: neoadj. Treatment<br>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<br>* Neoadjuvant CRT with external beam radiation (EBRT) delivering a total dose of 50.4 Gy over 28 days in 1.8 Gy fractions.<br>* Other names: EBRT;Drug: Gemcitabine neoadjuvant<br>* weekly Gemcitabine 300mg/m2 for 6 weeks neoadjuvant<br>* Other names: Gemzar;Procedure: Surgery<br>* Upfront pancreato-duodenectomy<br>* Other names: Tumor resection;Drug: Gemcitabine adjuvant<br>* 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<br>* Other names: 2',2'-Difluordesoxycytidin;|
| Active Comparator: Upfront Surgery<br>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<br>* Upfront pancreato-duodenectomy<br>* Other names: Tumor resection;Drug: Gemcitabine adjuvant<br>* 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<br>* Other names: 2',2'-Difluordesoxycytidin;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pancreatic cancer, surgery, chemoradiation, neoadjuvant treatment, overall survival