Due to limited investigations about radiation doses and the potential survival benefits, the pilot phase Ⅲ study was to compare the clinical outcomes of BED10 of 60-70Gy with those of ＞70Gy delivered by SBRT for LAPC, which may be conducive to a comprehensive understanding about an appropriate dose range for LAPC.
Study design, setting and participants
This is a multicenter, double blinded, randomized phase Ⅲ trial designed and supervised by investigators of Changhai Hospital. Patients aged from 18-75, with radiographically and biopsy confirmed LAPC, no prior treatment, and without metastasis and severe morbidities are enrolled in our study. Therefore, fine needle aspirations guided by endoscopic ultrasound is required for all patients. Details about the inclusion and exclusion criteria are shown in Table1. The definition of LAPC is referred to the NCCN guideline (Table 2).
Eligible participants would receive personal interviews with physicians for a detailed explanation of the whole study and related treatment. If the patients agree to participate in this clinical study, it is mandatory to obtain the written informed consents before the study. Afterwards, patients are required to complete the pretreatment evaluations including medical history, demographic data, physical examinations, blood routine tests, urine routine tests, liver and renal function tests, coagulation function tests, serum tumor marker (CA19–9) tests, blood amylase and urine amylase tests, enhanced CT and MRI. Participants will be randomly allocated into two group to receive SBRT and sequential chemotherapy. The ﬂow diagram of the study is illustrated in Figure 1.
The study is in line with the declaration of Helsinki. All patients will be informed of the details about the procedures, benefits and risks of chemotherapy and SBRT by physicians. Afterwards, patients could voluntarily decide to participate in the study. All physicians and patients involved in the study will be blinded to the allocations, and the randomization procedures will be carried out by researchers not involved in the study. Patients could withdraw from the study at any time for any reason. Physicians need to record all adverse effects promptly in case that the treatment may be stopped temporarily or patients may be excluded from the study due to chemotherapy or radiotherapy induced toxicities.
1. Radiation therapy
SBRT will be delivered by CyberKnife with Synchrony Respiratory Tracking system. Before CT simulations, 1 to 4 fiducial markers will be implanted using endoscopic ultrasound adjacent to or in the tumor. A plain CT and a contrast-enhanced pancreatic parenchymal CT will be performed for simulations. Vacuum-bags will be used for immobilizing the body, the arms and the legs. The image of contrast-enhanced MRI will be an auxiliary image for fusion. The radiation oncologists contour gross tumor volume (GTV), planning target volume (PTV) and organs at risk (OARs). GTV is defined as the visible lesion based on image examinations. PTV is delineated by uniform 3mm expansions of GTV. The participants are randomized into two groups, and receive the following regimens: Group1: SBRT with BED10 60-70Gy in 5-6 fractions; Group2: SBRT with BED10＞70Gy in 5-6 fractions. Ninety percent of PTV should be covered by the prescription dose. The prescription isodose line is limited to 78-80%, which would restrict the tumor Dmax. Dose constraints of normal tissues comply with AAPM TG-101 report.
Chemotherapy is performed after completion of SBRT. The initiation of gemcitabine plus albumin-bound paclitaxel is within 1 month after SBRT. Intravenous administration of gemcitabine (1000 mg/m2) plus albumin-bound paclitaxel (125 mg/m2) are delivered on days 1 and 8 during each 3-week cycle, which repeat for 4-6 cycles.
The schematic diagram for data collections and evaluations of efficacy and safety is shown in Table 3. All the pre-treatment data, and follow-up information of patients will be evaluated by physicians, and then checked again by the researchers not involved in the study to ensure accuracy and completeness. At the same time, All patients’ information will be strictly kept confidential. Treatment and follow-up data will be retrieved from the database when they need to be reviewed by the ethics committee or authorized researchers.
Participants will be monthly evaluated for CA19-9 level. Additionally, contrast enhanced CT and MRI would be performed every 2-3 months during follow-up or at the physician’s discretion. If CA19-9 continuously rises 3 months or new lesions are found by enhanced MRI or enhanced CT of the pancreas, chest CT, or preferable PET-CT is recommended.
The primary outcome is PFS. PFS is the time period from the initiation of SBRT to identification of disease progression including local relapse or metastases or death or the last follow-up. The secondary outcomes are LC, GI toxicity and OS. LC is the time period from the initiation of SBRT to identification of local progression according to RECIST criteria, version 1.1. Radiation-induced acute GI toxicities are determined by the Radiation Therapy Oncology Group, “Acute radiation morbidity scoring criteria”. Late GI toxicity morbidity scoring schema”. OS is the time period from the initiation of SBRT to the death by any cause or the last follow-up.
Normally and Non-normal distributed continuous data will be described by mean±SD and median (range), respectively, Categorical data will be expresses as n (%). Student t-test or Mann-Whitney U test was used for analysis in the case of normally or non-normally distributed continuous covariates. Categorical variables were compared using the χ2 test or Fisher’s exact test. PFS, OS and LC of two groups are estimated by the Kaplan-Meier method and compared via the log rank test. Univariate and multivariable hazard ratios are calculated with the Cox proportion hazard model. P values< 0.05 is considered statistically significant. Statistical analyses will be performed using SPSS software v18.0(SPSS Inc.,Armonk,NY).