Neoadjuvant Treatment in Resectable Pancreatic Cancer
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 "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.
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