Comparisons of different neoadjuvant chemotherapy regimens with or without stereotactic body radiation therapy for borderline resectable pancreatic cancer: study protocol of a prospective, randomized phase II trial (BRPCNCC-1)

The primary objective is to compare the OS of patients receiving neoadjuvant gemcitabine plus nab-paclitaxel versus gemcitabine plus nab-paclitaxel with SBRT versus S-1 plus nab-paclitaxel with SBRT for BRPC. The secondary objective is to compare DFS, pathological complete response rates and adverse effects of the three groups.

Neoadjuvant chemotherapy plus SBRT is superior to neoadjuvant chemotherapy alone regarding OS, while no significant difference is found between gemcitabine plus nab-paclitaxel with SBRT and S-1 plus nab-paclitaxel with SBRT.

This is a randomized, prospective, single center and phase III trial. Patients aged above 18, with radiographically and biopsy proven BRPC and without any prior treatment will be screened for eligibility. Therefore, all potential patients would receive fine needle aspirations guided by endoscopic ultrasound. Details about the inclusion and exclusion criteria are shown in Table 1. Additionally, though there are difficulties in defining this borderline resectable pancreatic cancer due to heterogeneity of definitions of this disease entity proposed by different institutions, it is likely that most of studies would employ the definition demonstrated in the NCCN guideline. Therefore, the definition of BRPC is referred to that clarified in the NCCN guideline (Table 2).

Eligible participants would receive personal interviews with physicians for a detailed explanation of the whole study and related treatment. It is mandatory to acquire the written informed consents before the study. Afterwards, patients are required to complete the pretreatment evaluations, including blood routine tests, liver and renal function tests, coagulation function tests, serum tumor marker (CA19–9) tests, enhanced CT and MRI, circulating cell free DNA (cfDNA), circulating tumor cells (CTC), DNA sequences of the specimens from fine-needle aspirations and pancreatic cancer-derived organoid cultures with specimens. In each group, participants will be randomized with a 1:1:1 allocation to receive gemcitabine plus nab-paclitaxel or gemcitabine plus nab-paclitaxel and SBRT or S-1 plus nab-paclitaxel and SBRT. Randomizations will be performed by a computer-generated random numbers table. After completion of the whole chemotherapy, patients will first receive PET-CT to exclude distant metastases and then undergo SBRT. Those with distant metastases will be precluded from the study and receive chemotherapy continuously. Likewise, patients confirmed with distant metastases after chemotherapy and SBRT will receive other aggressive chemotherapy regimens rather than surgical resections (Fig. 1).

The study is performed in accordance with the Declaration of Helsinki. All patients will be enrolled only after comprehensive information concerning the nature, scope, and possible consequences of the clinical trial has been provided to them in an understandable way by the physicians. Written informed consent will be obtained from each patient before the enrolment. During the study, details about the procedures, benefits and risks of chemotherapy, SBRT and surgery will be elucidated for those patients.

All physicians and patients involved in the study will be blinded to the allocations. Only researchers not involved in the study will be responsible for the randomization procedures. Additionally, patients could withdraw from the study at any time for any reason without any consequences. Clinicians are also required to record any 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 at the physicians’ discretion. Those dropping out of the study would receive other alternative treatment based on multidisciplinary approaches.

The protocol has been reviewed and approved by the institutional review board of our hospital (CHEC2018–176). The study has also been registered in ClinicalTrial.gov (NCT03777462).

All participants are allocated into the three groups randomly. Intravenous administration of gemcitabine (1000 mg/m²) or nab-paclitaxel (125 mg/m²) is initiated on day 1, 8 and 15 during each 4-week cycle, which will repeat for 3 cycles. S-1 is orally administrated at a dose of 80 mg/m² for 18 days followed by a 10-day rest, which also continues for 3 cycles.

SBRT is performed after completion of the chemotherapy. The protocol of SBRT is similar to our previous studies [10‐13]. Patients are required to be on fasting for 4–6 h before CT simulation. Vacuum bags are used for immobilization during SBRT. SBRT is delivered via Cyberknife, an image-guided frameless stereotactic robotic radiosurgery system (Accuray Corporation, Sunnyvale, California, USA). Before the simulation, fiducials should be implanted adjacent to the tumor guided by endoscopic ultrasound. Therefore, motion management during treatment would be performed by Synchrony® Respiratory Tracking System. A plain CT and an enhanced pancreatic parenchymal CT are performed for radiation treatment planning and target delineations. The scan range includes the whole pancreas, at least 10 cm above and below the tumor, with a slice thickness of 1 .5mm. Gross tumor volume (GTV) is delineated as a radiographically evident gross disease by the enhanced CT acquired from the portal-venous phase. At the discretion of the physician, clinical target volume (CTV) encompassing areas of the potential subclinical disease spread is also designated. In most cases, the CTV equals to GTV. A 2–5 mm expansion margin is included to determine the planning target volume (PTV). When tumors are adjacent to the critical organs, the expansion of GTV should be avoided at this direction. At least 90 % of PTV should be covered by the prescription dose. The prescribed dose is 7.5-8Gy/f for 5 fractions. Dose constraints of normal tissues are referred to the American Association of Physicists in Medicine guidelines in TG-101 [14].

Surgical resection is performed 3 weeks after SBRT. For the surgical approach of the tumor in the head of the pancreas, artery first approach pancreaticoduodenectomy is employed [15‐17]. Regarding the tumor in the body or tail of the pancreas, radical antegrade modular pancreatosplenectomy (RAMPS) is used [17, 18].

The schematic diagram for the timeline of data collections and evaluations of efficacy and safety is shown in Table 3. Pretreatment assessment will be performed and recorded by physicians. After randomizations, efficacy and toxicity of chemotherapy and SBRT and post-operative complications will also be evaluated and recorded by the clinicians. Furthermore, all information about the randomizations and data about the pretreatment assessment and follow-up will be firstly carefully checked by the physicians and re-checked by the researchers not involved in the study to promote data accuracy and completeness. And data entry into the database will be performed by the researchers.

The investigators will not assume any demands, including publishing or reporting of individual patient’s data, especially data required for this clinical trial, until a valid consent has been obtained. Patients’ data would be kept strictly confidential within the study, but their pseudonymous medical records and information would be extracted from the database and reviewed for trial purposes by authorized individuals other than their treating physicians.

Patients are required to receive regular follow-up 1 month, 3 months, 6 months, 1 year and 2 years after surgery. In each follow-up, patients will undergo physical examinations (ECOG, evaluations of symptoms and weight) and laboratory tests (including blood tests, liver and kidney functions, serum tumor biomarker). Imaging examinations will be performed 3 months, 6 months, 1 year and 2 years after surgery to evaluate efficacy. Post-operative complications would be evaluated 1 month and 3 months after surgical resection. Adverse effects of chemotherapy will be assessed according to The Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03). Radiation-induced acute toxicities are adverse effects that occur within 90 days after treatment, and determined by the Radiation Therapy Oncology Group, ‘Acute radiation morbidity scoring criteria’. If patients experience disease progression during follow-up, cfDNA and CTC would be performed to evaluate the tumor burden and identify genetic differences of the tumor cells before and after treatment as far as possible. Disease progression is determined by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria (v1.1).

The primary outcome is OS and 1-year and 2-year OS rate. OS is defined as the time interval from the time of surgical resection to the date of all-cause death or the last follow-up.

The secondary outcomes are DFS, pathological complete response rate, R0 resection rate, incidence of adverse effects. DFS is determined as the time interval from the date of surgery to the confirmation of recurrence at any sites or death from any cause, if this occurs before disease progression, or the last follow-up. The definition of pathological complete response is ypT0N0M0, which is no evidence of invasive tumor in the pancreas and the draining lymph nodes at the time of surgery. R0 resection is defined as both clear macroscopic and microscopic margins (≥1 mm).

Assuming, for the gemcitabine plus nab-paclitaxel group, a median 2-year OS rate of about 20%, we target a 10 and 15% relative improvement in 2-year OS rate for the group allocated to S-1 plus nab-paclitaxel with SBRT and gemcitabine plus nab-paclitaxel with SBRT over the gemcitabine plus nab-paclitaxel group, respectively. This would provide approximately 80% power with one-sided α of 0.025. Hence, the maximum number of required patients in each group is 73. Thereafter, when a 10% dropout rate is taken into account, the number of participants in each group is 81.