Gemcitabine/Capecitabine Followed by SBRT in Pancreatic Adenocarcinoma

Study Overview
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Brief Summary
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The current study seeks to further investigate the impact of up-front systemic therapy in combination with fractionated SBRT for potentially resectable, locally-advanced pancreatic adenocarcinoma.

Detailed Description
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All subjects will have a baseline CT or FDG-PET/CT prior to initiation of therapy. This will be done at the Hillman or in Radiation Oncology. Enrolled patients will undergo appropriate lab work and staging as described Albumin, alkaline phosphatase, glucose, electrolytes Ca 19-9 and CEA Due to an interaction of capecitabine and oral coumadin-derivative anticoagulants and risk of bleeding/thrombotic events, if a patient is on coumadin, frequent monitoring of INR and dose adjustments of anticoagulants must be exercised during protocol treatment. Alternatively, low molecular weight heparin may be substituted for oral anticoagulants Chemotherapy will be initiated consisting of gemcitabine 1000mg/m2 IV on day 1 and 8 of a 21 day cycle. Dosage for gemcitabine is described below using the Body surface area (BSA). BSA will be calculated from body weight in kg, recorded prior to every gemcitabine dosing, and height in cm, recorded at baseline. Premedication for Gemcitabine A standard, FDA-approved antiemetic medication will be administered to study participants at the discretion of the treating oncologist (investigator) one-half hour prior to the gemcitabine infusion. Examples of standard antiemetics include ondansetron (Zofran), granisetron (Kytril), dolasetron (Anzemet), compazine, and dexamethasone. The dosage and route of administration will be determined by the treating oncologist based upon the given clinical scenario. In addition, capecitabine 650mg/m2 PO will be taken twice daily on days 1-14 of a 3 week cycle. Four cycles total (12 weeks) of chemotherapy will be given. Dosage for capecitabine is described below using the Body surface area (BSA). BSA will be calculated from body weight in kg, recorded prior to every capecitabine dosing, and height in cm, recorded at baseline. Capecitabine (Xeloda; F. Hoffmann-La Roche AG, Basel, Switzerland) is supplied as ﬁlm-coated tablets in two dose strengths (150 and 500 mg); the closest practical dose (by rounding up or down) calculated on body-surface area based on a combination of tablets is taken within 30 minutes after the end of a meal. Patients will be assessed during chemotherapy with appropriate dose modifications made based on toxicity. Following the completion of chemotherapy, a new FDG-PET/CT or CT will be obtained to assess response and plan for SBRT. For those patients with SD, PR, or CR, SBRT will be planned and delivered. Fidiucial placement In addition, all patients will have fiducial markers placed for localization at time of SBRT. Three to five soft-tissue fiducials (markers) will be placed in and/or around the tumor, at least 1cm apart. Oftentimes, these are placed at the time of endoscopic ultrasound and biopsy for diagnosis. If that is not the case, patients will be scheduled for a repeat EUS and have the markers placed prior to CT or FDG-PET/CT simulation. Alternatively, fiducials may be placed at the time of staging laparoscopy. Stereotactic Body Radiotherapy Planning SBRT will be done in Shadyside Radiation Oncology. An SBRT plan will be created based on the disease contoured on the CT and PET. The plan will be to deliver fractionated SBRT to the isodose line best encompassing the PTV: 12 Gy x 3 fractions (36 Gy total) Careful evaluation of the each plan will be conducted by the radiosurgical team to ensure that normal tissues and critical structures tolerances are maintained. The maximum dose (in Gy) within the treatment volume (MD), prescriptions dose (PD), and the ratio of MD/PD (as a measure of heterogeneity within the target volume), prescription isodose volume (PIV in mm3), tumor volume (TV in mm3), and the ratio of PIV/TV (as a measure of dose conformity of the treatment relative to the target) will be recorded. Quality of Life Assessment Quality of life assessment using the Functional Assessment of Cancer Therapy - General (FACT-G) tool, which is a validated tool, will be administered to all subjects prior to treatment and at each follow-up visit. For patients with potentially resectable tumors, they will be assessed 10 - 12 weeks after SBRT by a multidisciplinary team including two expert pancreas surgeons and by FDG-PET/CT or CT scan. If deemed appropriate, patients with an adequate response will be taken for surgical resection. This will be performed as standard care. Time frames for chemotherapy and SBRT for 4 cycles of gemcitabine and capecitabine. The SBRT will not start until twelve weeks after the chemotherapy stops and will last approximately one week. Each cycle of gemcitabine and capecitabine is three weeks. Upon completion of treatment patients will be followed for survival for 24 months. They will be in the study for approximately two years give or take a few months. Interim medical history and physical examination 4 - 6 weeks after SBRT. Serum chemistry and electrolytes to include BUN, creatinine, sodium, potassium, bicarbonate, chloride, calcium, magnesium, glucose, total bilirubin, AST, ALT, alkaline phosphatase prior to chemotherapy treatments, 4 -6 weeks post-SBRT treatment, and then at follow-up as clinically indicated Hematologic studies to include CBC with differential and platelet count weekly during chemotherapy sessions and then repeated 4-6 weeks post-SBRT treatment and then at follow-up as clinically indicated CT or FDG-PET/CT scans (for consistency procedure done at screening/planning will continue in follow-up) will be obtained at 10-12 weeks post-treatment and will be reviewed for evidence of response. Subjects who demonstrate no evidence of distant metastases and meet RECIST criteria of partial response, complete response, or stable disease will be offered surgical exploration and attempted curative resection. Subjects demonstrating unresectable disease or progression of disease will be started on systemic chemotherapy at the discretion of the treating medical oncologist.

Official Title
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Induction Gemcitabine/Capecitabine Followed by SBRT in Pancreatic Adenocarcinoma A Prospective Evaluation in Patients With Locally Advanced Pancreas Cancer

Conditions
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Pancreatic Cancer

Intervention / Treatment
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* Drug: Gemcitabine
* Drug: Capecitabine
* Radiation: Stereotactic Body Radiation Therapy (SBRT)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically proven adenocarcinoma of the pancreas Subjects will be staged according to the 2010 AJCC staging system with pathologic stage T1-4, N0-1 being eligible; and have a primary tumor of the pancreas (i.e., pancreatic head, neck, uncinate process, body/tail Tumor must be deemed to be borderline resectable or locally advanced by radiographic criteria defined by Varadhachary et al.26 Final CT confirmation of surgical staging/eligibility will be by two expert pancreatic surgeons Disease confined to locoregional site confirmed by FDG-PET/CT or CT and diagnostic staging laparoscopy to ensure no occult peritoneal implants Disease must be encompassed in a reasonable SBRT portal as defined by the treating radiation oncologist Measurable disease on imaging studies (MRI, CT, FDG-PET/CT or physical exam), including maximum diameter/dimension, must be present for assessment of response Karnofsky performance status > 70 (ECOG 0-1) Age > 18 Estimated life expectancy > 12 weeks Patient must have adequate renal function as defined by serum creatinine<1.5mg/dl obtained within 28 days prior to registration Patient must have adequate bone marrow function as defined by absolute neutrophil count>1500/mcl and platelets>100,000/mcl, obtained within 28 days prior to registration Patient must have adequate hepatic function as defined by total bilirubin <1.5 x IULN(institutional upper limit of normal) and either SGOT or SGPT <2.5x IULN, obtained within 28 days prior to registration. Patient must be able to swallow enteral medications. Patient must not require a feeding tube. Patient must not have intractable nausea or vomiting, GI tract disease resulting in an inability to take oral medication, malabsorption syndrome, or uncontrolled inflammatory bowel disease (Chron's, ulcerative colitis). Diabetes must be controlled prior to FDG-PET/CT scanning (blood glucose <200 mg/dL) Ability to provide written informed consent Patient must not have uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, history of myocardial infarction or cerebrovascular accident within 3 months prior to registration, uncontrolled diarrhea, or psychiatric illness/social situations that would limit compliance with study requirements. Patient must not be pregnant because of the risk of harm to the fetus. Nursing women may participate only if nursing is discontinued, due to the possibility of harm to nursing infants from the treatment regimen. Women/men of reproductive potential must agree to use an effective contraception method. Exclusion Criteria: Non-adenocarcinomas, adenosquamous carcinomas, islet cell carcinomas, cystadenomas, cystadenocarcinomas, carcinoid tumors, duodenal carcinomas, distal bile duct, and ampullary carcinomas are not eligible. Evidence of distant metastasis on upright chest x-ray (CXR), computed tomography (CT) or other staging studies Subjects with recurrent disease Prior radiation therapy to the upper abdomen or liver Prior chemotherapy Subjects in their reproductive age group should use an effective method of birth control. Subjects who are breast-feeding, or have a positive pregnancy test will be excluded from the study Any co-morbidity or condition of sufficient severity to limit full compliance with the protocol per assessment by the investigator Concurrent serious infection Previous or current malignancies of other histologies within the last 5 years, with the exception of cervical carcinoma in situ, adequately treated basal cell or squamous cell carcinoma of the skin, and treated low-risk prostate cancer.

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 |
| --- | --- |
| Other: Gem, Xeloda, SBRT<br> | Drug: Gemcitabine<br>* Gemcitabine will be administered for 2 weekly doses every 3 weeks commencing 12 weeks prior to stereotactic radiosurgery as follows: Gemcitabine 1,000 mg/m2 IV over 30 minutes on Day 1, and 8 of 21- day cycle. This will be done for up to 4 cycles.<br>* Other names: Gemzar;Drug: Capecitabine<br>* Capecitabine will be taken orally twice daily on days 1-14 every 3 weeks for 4 cycles (12 weeks) prior to stereotactic radiosurgery as follows: Capecitabine 650 mg/m2 twice daily for days 1-14 every 3 weeks for up to 4 cycles.<br>* Other names: Xeloda;Radiation: Stereotactic Body Radiation Therapy (SBRT)<br>* Fractionated SBRT will be delivered to patients that have stable disease, partial response, or complete response after chemo in the following manner: 12 Gy x 3 fractions (36 Gy total) This will be given every other day.<br>* Other names: SBRT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local Progression-free Survival (LPFS) | LPFS is defined as the time from enrollment to first documentation of progressive disease (PD) in the target lesion. For patients that undergo surgical resection, local progression will be defined as disease recurrence detected on follow-up imaging (CT or FDG-PET/CT) that is located within the SBRT target volume. Death or development of distant disease is not regarded as an event. Per Response Evaluation Criteria in Solid Tumors (RECIST) v1.0, progressive disease is defined as at least a 25% increase in the longest diameter of a lesion, taking as reference the longest diameter recorded since the treatment started. | Up to 32 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) (Neoadjuvant Chemotherapy) | Percentage of participants with response per RECIST v1.0. Per RECIST v1.0: Complete Response (CR): the disappearance of a lesion; Near Complete Response (NCR): at least an 80% decrease in the longest diameter of a lesion, taking as reference the longest diameter recorded since the treatment started. Partial Response (PR): at least a 30% decrease in the longest diameter of a lesion, taking as reference the longest diameter recorded since the treatment started. | Up to 24 months | 
| Objective Response Rate (ORR) (Surgery After Chemotherapy and SBRT) | Percentage of participants with response per RECIST v1.0. Per RECIST v1.0: Complete Response (CR): the disappearance of a lesion; Near Complete Response (NCR): at least an 80% decrease in the longest diameter of a lesion, taking as reference the longest diameter recorded since the treatment started. Partial Response (PR): at least a 30% decrease in the longest diameter of a lesion, taking as reference the longest diameter recorded since the treatment started. | Up to 24 months | 
| Overall Survival (OS) | The (median) length of time from enrollment to confirmed death from any cause. | Up to 32 months | 
| Time to Progression (TTP) | The (median) length of time from enrollment to disease progression per Response Evaluation Criteria in Solid Tumors (v1.0). Per RECIST, Progressive Disease (PD) is defined at least a 25% increase in the longest diameter of a lesion, taking as reference the longest diameter recorded since the treatment started. For lesions without size response the maintenance of CA 19-9 level above the normal limits indicates disease progression. | Up to 5 years | 
| The Functional Assessment of Cancer Therapy - General (FACT-G) | The Functional Assessment of Cancer Therapy - General (FACT-G) is a self-administered, 27-item questionnaire designed to measure four domains of HRQOL in cancer patients: Physical, social, emotional, and functional well-being. Quality of Life (QOL) evaluation will be administered prior to SBRT, after completion of SBRT, and at each follow-up. Scaling of items: Five-point scale for each questions from 0 (not at all) to 4 (very much); overall scoring 0-108. Higher scores indicated better quality of life. | Baseline; 2 - 4 weeks post chemotherapy; 4-6 weeks post SBRT; after surgery (up to 24 months) | 
| Number of Participants Able to Undergo a Margin-negative Resection After Neoadjuvant Therapy | Number of patients that are able to undergo a margin-negative resection after neoadjuvant therapy. Surgical evaluation: pathology records reviewed by operating surgeon to determine margin status as negative (not close (1-2.5mm), microscopically positive, and/or grossly positive). | Up to 24 months | 
| Acute Toxicities Associated With SBRT | Percentage of patients that experience treatment-related toxicities as graded according to Common Terminology Criteria for Adverse Events (CTCAE v4), within 3 months after treatment, by grade. Patients were monitored for potential toxicity throughout treatment. | Up to 3 months following SBRT treatment | 
| Late Toxicities Associated With SBRT | Percentage of patients that experience treatment-related toxicities as graded according to Common Terminology Criteria for Adverse Events (CTCAE v4), greater than 3 months after treatment, by grade. Patients were monitored for potential toxicity throughout treatment. | From 3 months following SBRT treatment up to 24 months | 
| Role of FDG-PET/CT | 18F-FDG response measured using European Organization for Research and Treatment of Cancer (EORTC) 1999. Number of patients with non-FDG avid tumors with response to therapy using semi-quantitative SUV (standard uptake value) analysis based on lean body mass and/or body surface area is used in determining 18F-FDG uptake. [18F]-FDG uptake may provide an early, indication of the tumoricidal effect of anticancer agents. | Up to 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pancreas