Combination of SBRT With Sequential S-1 for Treating Locally Advanced Pancreatic Cancer

Study Overview
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Brief Summary
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The safety and efficacy of combination of SBRT with sequential S-1 in treating patients with locally advanced pancreatic cancer and poor medical conditions will be evaluated.

Detailed Description
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Although the incidence rate of pancreatic cancer is not as high as that of other gastrointestinal carcinoma in China, the cancer mortalities of males and females ranked the sixth and seventh respectively in 2013, with a surprising low 5-year survival rate (<5%). Only 15%-20% patients are suitable for surgeries among those first diagnosed with pancreatic cancer and the 5-year survival rate of patients with R0 resection is still less than 20%. Therefore, better efficacy is not available via surgeries alone resulting in great emphasis on adjuvant chemoradiotherapy. In 1997, gemcitabine was confirmed to be the standard chemotherapy for pancreatic cancer. However, it has not been proved that gemcitabine significantly improved prognosis in long term follow-up while some patients are refractory to gemcitabine. Hence, development of more effective chemotherapy is urgent. S-1 is the prodrug of 5-fluorouracil (5-FU), comprised of tegafur, gimeracil (dihydropyrimidine dehydrogenase inhibitor) and oteracil (the inhibitor of phosphorylation in gastrointestinal tract) with a ratio of 1:0.4:1. The first phase II clinical trials showed good clinical efficacy with S-1.Moreover, Ueno et al. identified better objective response rates with S-1 than those with gemcitabine. Besides, S-1 is not inferior to gemcitabine regarding to overall survival rates and progression free survival rates. And significant improvement of progression free survival rates can be achieved by combination of S-1 and gemcitabine. There was no difference between incidence rates of adverse effects of S-1 and gemcitabine, with more gastrointestinal toxicities with S-1 while more hematologic toxicities with gemcitabine. Therefore, S-1 is an alternative for treating locally advanced or metastatic pancreatic cancer, especially for those resistant to gemcitabine. Although there are no phase III studies on S-1, phase II studies have already shown better disease control rates (52%-58%), median overall survival time (4.5-6.3 months) and tolerable adverse effects in advanced pancreatic cancer resistant to gemcitabine treated with S-1. Though S-1 is appropriate for advanced pancreatic cancer, it is not superior to gemcitabine with respect to clinical efficacy. In addition, fewer encouraging results are gained with combination of S-1 and other drug. As a result, S-1 combined with radiotherapy is gradually applied in treatment of pancreatic cancer. 5-FU was proved to be radiosensitive thus improving clinical efficacy. S-1 combined with radiotherapy has demonstrated better prognosis with the median overall survival time of 12.9-16.8 months. Furthermore, some patients can be operable after S-1 and radiotherapy. Compared with conventional radiation, a single-fraction dose and total dose of target volume can be increased in stereotactic body radiation therapy (SBRT). In addition, doses of organs at risk would be reduced, thus effectively improving local control rates and reducing radiation related toxicity. Shorter courses of SBRT also enhance patients' compliance and render the initial of other treatment on schedule possible. Nevertheless, there are few studies focusing on S-1 combined with SBRT for locally advanced pancreatic cancer. Especially for patients with poor medical coonditions, though gemcitabine alone is recommended in the NCCN guideline, S-1 may be a better option due to more adverse effects induced by gemcitabine in Asian. Additionally, local ablative treatment combined with chemotherapy may provide more survival benefits for those patients. Hence, efficacy of combination of S-1 and SBRT needs to be further confirmed. Based on our experience in treating locally advanced pancreatic cancer, SBRT combined with sequential S-1 as the initial treatment for patients with locally advanced pancreatic cancer and poor medical conditions is proposed to evaluate its clinical efficacy. 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. The total doses depend on patients' medical conditions, ranging from 35Gy-40Gy/5Fx. Patients receive 80 mg of S-1 per square meter of body surface area twice a day for 4 weeks, followed by 2 weeks of rest as one course, which would repeat for six cycles.The initiation of S-1 is one month after SBRT.

Official Title
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Stereotactic Body Radiation Therapy With Sequential S-1 for Patients With Locally Advanced Pancreatic Cancer and Poor Medical Conditions --a Phase II Clinical Trial

Conditions
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Pancreatic Cancer

Intervention / Treatment
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* Other: combination of Cyberknife with S-1


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Locally advanced pancreatic cancer proved by CT or MRI and biopsy Without any other treatment before SBRT A life expectancy of >3months ECOG: 2 or 3 points Age of more than 18 years old Blood routine examination: Absolute neutrophil count (ANC) ≥ 1.5 ×10^9 cells/L, leukocyte count≥ 3.5 ×10^9 cells/L, platelets ≥ 70×10^9 cells/L, hemoglobin ≥ 8.0 g/dl Liver and kidney function tests: Albumin > 2.5 g/dL, total bilirubin < 3 mg/dL, creatinine < 2.0 mg/dL, AST<2.5 × ULN(Upper Limit of Normal)(0-64U/L), ALT<2.5 × ULN(0-64U/L) INR < 2 (0.9-1.1) Ability of the research subject or authorized legal representative to understand and the willingness to sign a written informed consent document. Exclusion Criteria: Prior surgery, chemotherapy or radiation for the pancreatic cancer Evidences of metastatic disease such as nodal or distant metastases by abdomen CT and chest CT or FDG PET-CT Contraindication to receiving radiotherapy ECOG: 0-1 point Age<18 Abnormal results of blood routine examinations and liver and kidney tests Patients with active inflammatory bowel diseases or peptic ulcer Gastrointestinal bleeding or perforation within 6 months Heart failure: NYHA III-IV Women who are pregnant Participation in another clinical treatment trial while on study Patients in whom fiducial implantation was not possible Inability of the research subject or authorized legal representative to understand and the willingness to sign a written informed consent document.

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
Interventional Model Description: stereotactic bodt radiation therapy plus sequential S-1 for locally pancreatic cancer
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Combination of Cyberknife with S-1<br>Patients with locally advanced pancreatic cancer meeting all inclusion criteria will receive combination of Cyberknife with S-1. | Other: combination of Cyberknife with S-1<br>* Radiation therapy combined with chemotherapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| One-year Overall Survival Rate | One-year overall survival rate is calculated by the ratio of number of patients surviving more than 1 year to the total number of patients enrolled. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Acute Toxicities Following SBRT | The acute toxicities are determined by RTOG Acute Radiation Morbidity Scoring Criteria. | Within 90 days after completion of SBRT | 
| Number of Participants With Late Toxicities Following SBRT | The late toxicities are determined by RTOG/EORTC Late Radiation Morbidity Scoring Criteria. | 90 days after SBRT | 
| The Median Progression Free Survival Time Will be Determined. | Progression-free survival is the time from the date of enrollment to the confirmation of disease progression at any sites, including local progression or metastasis, or death from any causes, if this occurred before disease progression. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | 3 years | 
| The Quality of Life Will be Analyzed. | The analysis of quality of life is based on The European Organization for Reasearch and Treatment of Cancer (EORTC): Quality of Life Questionnare-Core 30 (QLQ-C30). Higher scores in function domains and global health status indicate better quality of life, while higher scores in symptom domains imply worse quality of life. The scale range of all domains of QLQ-C30 is 0-100 (the minimum and maximum score is 0 and 100 points, respectively). | 1 years | 
| Median Overall Survival Will be Determined. | Median overall survival is calculated by Kaplan-Meier method. | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stereotactic body radiation therapy, locally advanced pancreatic cancer, poor medical conditions, S-1