Clinical trial NCT02704143: Combination of SBRT With Sequential S-1 for Treating Locally Advanced Pancreatic Cancer
Official title: Stereotactic Body Radiation Therapy With Sequential S-1 for Patients With Locally Advanced Pancreatic Cancer and Poor Medical Conditions --a Phase II Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Pancreatic Cancer
Keywords: stereotactic body radiation therapy
S-1
locally advanced pancreatic cancer
poor medical conditions
Lead sponsor: Changhai Hospital
Sponsor class: OTHER
First posted: 2016-03-09
Enrollment: 63
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: stereotactic bodt radiation therapy plus sequential S-1 for locally pancreatic cancer
Primary purpose: TREATMENT

Brief summary: 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: 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:

1. 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.
2. 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.
3. A body fixation (vacuum-bag) will be used in immobilizing the body, the arms (both arms are along the body) and the legs.
4. The total doses depend on patients' medical conditions, ranging from 35Gy-40Gy/5Fx.
5. 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.

Eligibility criteria: Inclusion Criteria:

1. Locally advanced pancreatic cancer proved by CT or MRI and biopsy
2. Without any other treatment before SBRT
3. A life expectancy of \>3months
4. ECOG: 2 or 3 points
5. Age of more than 18 years old
6. 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
7. 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)
8. INR \< 2 (0.9-1.1)
9. Ability of the research subject or authorized legal representative to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

1. Prior surgery, chemotherapy or radiation for the pancreatic cancer
2. Evidences of metastatic disease such as nodal or distant metastases by abdomen CT and chest CT or FDG PET-CT
3. Contraindication to receiving radiotherapy
4. ECOG: 0-1 point
5. Age\<18
6. Abnormal results of blood routine examinations and liver and kidney tests
7. Patients with active inflammatory bowel diseases or peptic ulcer
8. Gastrointestinal bleeding or perforation within 6 months
9. Heart failure: NYHA III-IV
10. Women who are pregnant
11. Participation in another clinical treatment trial while on study
12. Patients in whom fiducial implantation was not possible
13. Inability of the research subject or authorized legal representative to understand and the willingness to sign a written informed consent document.

Primary outcomes:
measure: One-year Overall Survival Rate
timeFrame: 1 year
Secondary outcomes:
measure: Number of Participants With Acute Toxicities Following SBRT
timeFrame: Within 90 days after completion of SBRT
measure: Number of Participants With Late Toxicities Following SBRT
timeFrame: 90 days after SBRT
measure: The Median Progression Free Survival Time Will be Determined.
timeFrame: 3 years
measure: The Quality of Life Will be Analyzed.
timeFrame: 1 years
measure: Median Overall Survival Will be Determined.
timeFrame: 3 years
Other outcomes:
Locations:
city: Shanghai
country: China
facility: Changhai hospital
state: Shanghai
Study officials:
affiliation: Changhai Hospital
name: Huo Jun Zhang, MD., PH.D
role: PRINCIPAL_INVESTIGATOR
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