Phase ǀ Study on Pancreatic Cancer Treated by CyberKnife

Study Overview
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Brief Summary
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The maximum tolerated dose on locally advanced unresectable pancreatic tumor treated with CyberKnife SBRT will be evaluated.

Detailed Description
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Pancreatic cancer is the fourth-leading cause of cancer-related death in the world. It is characterized by metastatic spread and local failure and seldom detected in its earlier stages. For locally advanced stage pancreatic cancer, the complete surgical removal is hard to achieve. Stereotactic body radiotherapy (SBRT) with CyberKnife for unresectable pancreatic tumor is a relatively new treatment option made available because of significant improvements in diagnostic imaging and radiation delivery techniques. Different from the conventional radiotherapy, radiation dose is delivered in fewer fractions and higher fractional doses in SBRT. Gurka (1) reported that 14 patients received SBRT with prescription dose of 25 Gy in five fractions with biologically equivalent doses (BED) of α/β=10 in correspondence to 37.5Gy. Grade 1 to 2 gastrointestinal toxicity (no grade 3 or 4 radiation-related toxicities) was observed two weeks after treatment. Two patients had a partial response, and 12 patients were with stable diseases. In the previous dose escalation study, a single fraction up to15 Gy, 20 Gy, 25 Gy which is an equivalent BED10 to 37.5 Gy, 60 Gy, 87.5 Gy respectively is recommended by Koong AC (2) and his team. Even though the local control rate is 100%, the follow up is short and the sample size of 15 patients is relatively small. Moreover, the late toxicity is not investigated. And with single fraction scheme, higher late gastrointestinal (GI) toxicities were reported (2,3,4). In the meanwhile, investigators (5, 6) from South Korea examined that a Dmax of 35Gy and 38Gy in 3 fractions (BED10 to 75.8Gy and 86.1Gy) of SBRT correlated with a 5% and 10% rate of grade 3 of gastroduodenal toxicity for abdominal malignant tumor, respectively. Chuong (7) used 5 fractions to potentially decrease the risk of late normal tissue injury compared with 1 to 3 fractions commonly used in other institutions. Assuming α/β=3, the BED3 delivered to normal tissue in this study (using a mean 36.4 Gy in 5 fractions to the high dose PTV) was 125 Gy, which is lower than the mean BED3 from other series, the corresponding values from Boston and Stanford were 153.7 Gy (mean, 32.96 Gy in 3 fractions) and 233.3 Gy (mean, 25Gy in 1 fraction), respectively (8, 9). And a relatively lower incidence of grade ≥3 late adverse effects (5.3% VS 9%) was observed. Since the treatment modality and dose are still under exploratory stage, we propose to conduct a Phase I study determining the maximum tolerated dose of CyberKnife SBRT on dose escalation for the treatment of locally advanced pancreatic tumor based on a 5 fractions treatment regimen. A prescription dose of 35-47.5 Gy in five fractions was chosen, with an equivalent to the traditional dose of 2 Gy in 25-39 fractions of BED10. And this is assumed to be the safe and effective dose for unresectable pancreatic cancer patients. Study Procedure: CyberKnife SBRT body fixation (vacuum-bag) will be used in immobilizing the body, the arms and the legs. Patients will undergo a plain CT as well as an enhanced pancreatic parenchymal CT for radiation treatment planning and target delineation. SBRT will be delivered on CyberKnife with Synchrony Respiratory Tracking system. The tumor will be tracked with implanted fiducial markers by Fiducial Tracking System. Treatment will be delivered in 5 fractions within 1 to 2 weeks at the discretion of the investigator. A body fixation (vacuum-bag) will be used in immobilizing the body, the arms (both arms are along the body) and the legs.

Official Title
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Mono-Center Phase ǀ Study on Dose Escalation of Stereotactic Body Radiotherapy (SBRT) Treating Pancreatic Cancer Patients With CyberKnife

Conditions
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Pancreatic Tumor

Intervention / Treatment
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* Device: CyberKnife


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Unresectable pancreatic adenocarcinoma or unsuitable/unwilling for resection which is proved by biopsy. A life expectancy of >3months Eastern Cooperative Oncology Group (ECOG) status ≤2 Tumor size < 5 cm Tumor location: Head of pancreas Patients must be able to undergo contrast enhanced CT for planning Absolute neutrophil count (ANC) ≥ 1.5 ×109 cells/L Leukocyte count≥ 3.5 ×109cells/L Platelets ≥ 70×109cells/L Hemoglobin ≥ 8.0 g/dl Albumin > 2.5 g/dL Total bilirubin < 3 mg/dL Creatinine < 2.0 mg/dL INR < 2 (0.9-1.1) Aspartate transaminase (AST) <2.5 × Upper Limit of Normal (ULN )(0-64U/L) Alanine aminotransferase (ALT) <2.5 × ULN(0-64U/L) Both men and women and members of all races and ethnic groups are eligible for this study Ability of the research subject or authorized legal representative to understand and the willingness to sign a written informed consent document Tumor markers and lab test should be done less than 1 week before recruitment Exclusion Criteria: Prior surgery, chemotherapy or radiation for the pancreatic tumor Prior radiotherapy to the upper abdomen, evidence of metastatic disease such as nodal or distant metastases by abdomen CT and chest CT or FDG PET-CT Contraindication to receiving radiotherapy Distance between gross tumor volume (GTV) (lesion) and luminal structures (including liver, stomach, duodenum, small or large bowel) is<5 mm Women who are pregnant Participation in another clinical treatment trial while on study Patients in whom fiducial implantation was not possible

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Maximal tolerated dose with CyberKnife<br>SBRT will be delivered in 5 fractions within 1 to 2 weeks by the following schedule: Doses of 7 Gy, 7.5 Gy, 8 Gy, 8.5 Gy, 9 Gy, 9.5 Gy x 5 with BED10 in correspondence to 59.5 Gy, 65.6 Gy, 72 Gy, 78.6 Gy, 85.5 Gy, 92.6 Gy respectively while meeting with normal tissue constraints. A minimum of three patients will be included for each dosage level. And an interval is four weeks between each dose level. In case patient presents III/IV GI toxicity, three additional patients will be included at the same dose level. The Maximal Tolerated Dose will be defined as the dose for which at least 2 patients in 3, or at least 3 patients in 9, will present with a limiting toxicity. | Device: CyberKnife<br>* Radiation Therapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The maximum tolerated dose will be determined | The maximal tolerated dose will be defined as the dose for which at least 2 patients in 3, or at least 3 patients in 9, will present with a limiting toxicity. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The acute toxicities following SBRT will be determined. | The acute toxicities are determined by RTOG Acute Radiation Morbidity Scoring Criteria. | 1 year | 
| The late toxicities following SBRT will be determined. | The late toxicities are determined by RTOG/EORTC Late Radiation Morbidity | 1 year | 
| Pain intensity will be determined. | Pain intensity is assessed by the numeric rating scales 0-10 | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Stereotactic Body Radiotherapy (SBRT), CyberKnife, Dose Escalation