Perioperative Therapy for Resectable Pancreatic Cancer

Study Overview
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Brief Summary
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This phase II trial studies how well giving combination chemotherapy together with intensity-modulated radiation therapy (IMRT) and surgery works in treating patients with localized pancreatic cancer that can be removed by surgery. Drugs used in chemotherapy, such as gemcitabine hydrochloride, docetaxel, capecitabine, and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Specialized radiation therapy, such as IMRT, that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Giving more than one drug (combination chemotherapy) together with intensity-modulated radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving chemotherapy after surgery may kill any tumor cells that remain after surgery.

Detailed Description
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PRIMARY OBJECTIVES: I. To estimate the median overall survival of patients with adenocarcinoma of the pancreas treated with induction chemotherapy, neoadjuvant chemoradiotherapy, surgical resection and adjuvant chemotherapy. SECONDARY OBJECTIVES: I. To determine the percent of patients surviving at annual intervals through five years. II. To determine the median recurrence free survival following pancreaticoduodenectomy. III. To determine the clinical response rate to neoadjuvant chemotherapy and chemoradiotherapy. IV. To determine the pathologic response rate to neoadjuvant chemotherapy and chemoradiotherapy. V. To determine the cancer antigen (CA) 19-9 tumor marker response rate to neoadjuvant chemotherapy and chemoradiotherapy. VI. To determine the surgical completion rate and complication rate following neoadjuvant chemotherapy and chemoradiotherapy. VII. To determine the frequency and severity of toxicities associated with this treatment regimen. OUTLINE: INDUCTION CHEMOTHERAPY: Patients receive gemcitabine hydrochloride intravenously (IV) over 75 minutes and docetaxel IV over 30 or 60 minutes on days 4 and 11. Patients also receive capecitabine orally (PO) twice daily (BID) on days 1-14. Treatment repeats every 21 days for 3 courses in the absence of disease progression or unacceptable toxicity. NEOADJUVANT CHEMORADIOTHERAPY: Beginning no more than 14 days after completion of induction chemotherapy, patients receive capecitabine PO BID on days 1-14 and oxaliplatin IV over 2 hours on days 1 and 8. Patients also undergo IMRT once daily on days 1-5 and 8-13. SURGICAL RESECTION: Approximately 2-6 weeks after completion of neoadjuvant chemoradiotherapy, patients undergo pancreaticoduodenectomy. ADJUVANT CHEMOTHERAPY: Beginning 4-10 weeks after surgery, patients receive gemcitabine hydrochloride IV over 30 minutes and oxaliplatin IV over 2 hours on day 1. Treatment repeats every 14 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients then receive gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Treatment repeats every 28 days for 2 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months.

Official Title
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A Phase II Study Induction Chemotherapy, Neoadjuvant Chemoradiotherapy, Surgical Resection and Adjuvant Chemotherapy for Patients With Locally Advanced, Resectable Pancreatic Adenocarcinoma

Conditions
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Adenocarcinoma of the Pancreas, Stage IA Pancreatic Cancer, Stage IB Pancreatic Cancer, Stage IIA Pancreatic Cancer, Stage IIB Pancreatic Cancer

Intervention / Treatment
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* Drug: gemcitabine hydrochloride
* Drug: docetaxel
* Drug: capecitabine
* Radiation: intensity-modulated radiation therapy
* Drug: oxaliplatin
* Procedure: pancreatic surgical procedure
* Procedure: therapeutic conventional surgery
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically or cytologically confirmed diagnosis of localized, resectable or borderline resectable, pancreatic adenocarcinoma T1-T3, N0-N1, M0; stage is determined by helical multi-phase computed tomography (CT) and/or endoscopic ultrasound according to published guidelines; resectability is determined by the treating surgeon and published guidelines (National Comprehensive Cancer Network) Resectable Disease- Head/Body/Tail of pancreas: No distant metastases Clear fat plane around celiac and superior mesenteric arteries (SMA) Patent superior mesenteric vein (SMV) and portal vein (PV) Borderline Resectable Disease -Head/Body of pancreas: Tumor abutment on SMA SMV/portal vein impingement or occlusion if involving only a short segment, with open vein both proximally and distally (if proximal vein is occluded up to the portal vein branches then disease is unresectable) Colon or mesocolon invasion Gastroduodenal artery (GDA) encasement up to origin at hepatic artery Tail of pancreas: Adrenal, colon or mesocolon, or kidney invasion Preoperative evidence of biopsy-positive peripancreatic lymph node No prior therapy for pancreatic cancer Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) Leucocytes >= 3,000/uL Absolute Neutrophil Count >= 1,500/uL Platelets >= 100,000/uL Total Bilirubin: If within normal limits (WNL) to =< 2.0, the subject is eligible If > 2.0 - < 6.0, subject is eligible IF they have a biliary stent and total bilirubin is decreasing If >= 6.0, subject is not eligible Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvic transaminase [SGPT]) =< 2.5 X institutional upper limit of normal or =< 1.5 X upper limit of normal (ULN) if alkaline phosphatase (Alk Phos) > 2.5 X ULN or if the subject has a biliary stent and the liver function tests (LFTs) are decreasing the subject is eligible Creatinine clearance >= 30% Negative pregnancy test for women of childbearing potential; women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately Ability to swallow and retain oral medication Ability to understand and willingness to sign a written informed consent document Exclusion Criteria: Patients may not be receiving any other investigational agents Histology other than adenocarcinoma Patients with permanently unresectable pancreatic adenocarcinoma as determined by the treating physician and published guidelines (National Comprehensive Cancer Network) Unresectable disease Head of pancreas: Distant metastases (includes celiac and/or para-aortic) SMA, celiac encasement SMV/portal occlusion Aortic, inferior vena cava (IVC) invasion or encasement Invasion of SMV below transverse mesocolon Body of pancreas: Distant metastases (includes celiac and/or para-aortic); at the discretion of the treating surgeon, body and tail lesions that have positive celiac and/or para-aortic nodes in close vicinity to the primary may be borderline rather than unresectable SMA, celiac, hepatic encasement SMV/portal extended occlusion Aortic invasion Tail of pancreas: Distant metastases (includes celiac and/or para-aortic) SMA, celiac encasement Rib, vertebral invasion History of allergic reactions attributed to compounds of similar chemical or biologic composition to gemcitabine, docetaxel, capecitabine, oxaliplatin or other agents used in the study Patients who have received prior chemotherapy or radiotherapy for the diagnosis of pancreatic cancer Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Inability to comply with study and/or follow-up procedures Pregnancy or lactation Human immunodeficiency virus (HIV)-positive patients receiving combination anti-retroviral therapy

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (chemotherapy, radiation, pancreaticoduodenectomy)<br>See Detailed Description | Drug: gemcitabine hydrochloride<br>* Given IV<br>* Other names: Gemzar;Drug: docetaxel<br>* Given IV<br>* Other names: TXT;Drug: capecitabine<br>* Given PO<br>* Other names: Xeloda;Radiation: intensity-modulated radiation therapy<br>* Undergo IMRT<br>* Other names: IMRT;Drug: oxaliplatin<br>* Given IV<br>* Other names: L-OHP;Procedure: pancreatic surgical procedure<br>* Undergo pancreaticoduodenectomy<br>* Other names: pancreatic surgery;Procedure: therapeutic conventional surgery<br>* Undergo therapeutic conventional surgery<br>Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Overall Survival of Patients With Adenocarcinoma of the Pancreas | Time at which Kaplan-Meier estimate of overall survival drops below 50% | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Patients Surviving at 5 Years | Kaplan-Meier estimate of overall survival at 5 years | Up to 5 years | 
| Median Recurrence Free Survival Following Pancreaticoduodenectomy | The appearance of radiographic findings consistent with recurrent tumor at the local resection site or at a distant location is considered a radiographic recurrence. | From the date of pancreaticoduodenectomy to date of first observation of radiographic recurrence or death due to any cause, assessed up to 7 years | 
| Clinical Response Rate to Neoadjuvant Chemotherapy and Chemoradiotherapy | Assessed using the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee. | Up to 7 years | 
| Pathologic Response Rate (Complete, Near-complete, Partial) to Neoadjuvant Chemotherapy and Chemoradiotherapy | The resected pancreaticoduodenectomy specimen and accompanying lymph nodes will be staged according to American Joint Committee on Cancer 6th Edition incorporating the prefix y to indicate a specimen status-post neoadjuvant treatment (ypTNM). Cancer 2012;118:1382-90 | Up to 7 years | 
| CA 19-9 Tumor Marker Response Rate to Neoadjuvant Chemotherapy and Chemoradiotherapy | Biochemical response is a decrease of >= 50% of CA 19-9 serum tumor marker in patients with elevated CA 19-9 at baseline. | Up to 26 weeks after surgery | 
| Surgical Completion Rate and Complication Rate |  | Up to 6 weeks following the completion of chemoradiotherapy | 
| Frequency and Severity of Toxicities Associated With This Treatment Regimen as Assessed by NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 |  | Up to 26 weeks after surgery (the end of adjuvant chemotherapy) | 
| Percent of Patients Surviving at Annual Intervals |  | 5 years |