Patient population
Patients who were radiologically and histologically diagnosed with primary metastatic pancreatic adenocarcinoma between July 2012 and April 2017 were enrolled in this multicenter, single-arm, prospective phase II study. Inclusion criteria included an age of 18 years or older and an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1 or 2, with at least one measurable metastatic lesion and adequate hematological, liver, and renal functions (hemoglobin ≥ 90 g/L, neutrophil count ≥ 2.0 × 109/L, platelet count ≥ 90 × 109/L, total bilirubin ≤ 1.2 × upper limit of normal, aspartate transaminase and alanine transaminase ≤ 2.5 × upper limit of normal, and creatinine ≤ 1.25 × upper limit of normal). Prior adjuvant therapy (including adjuvant radiotherapy or chemotherapy > 4 weeks) was allowed. Patients with postoperative recurrence were also enrolled.
Exclusion criteria were an age of 76 years or older, pancreatic malignancies other than adenocarcinoma, a history of other types of cancer, active and uncontrolled medical diseases such as severe sepsis and septic shock, symptomatic peripheral neuropathy > grade 2, a history of palliative radiotherapy/immunotherapy, and pregnancy or breastfeeding women. Written informed consent was obtained from all patients. The study was approved by the independent ethics committees of Sun Yat-sen University Cancer Center, Tianjin Medical University Cancer Institute and Hospital, and The First People’s Hospital of Foshan and was performed in accordance with the Declaration of Helsinki.
Treatment and assessment
Patients were given a 30-min intravenous infusion of antiemetic and then treated with modified FOLFIRINOX (a 2-h intravenous infusion of oxaliplatin at 65 mg/m2, immediately followed by a 2-h intravenous infusion of l-leucovorin at 200 mg/m2, a 1.5-h intravenous infusion of irinotecan at 150 mg/m2, and a 46-h continuous infusion of fluorouracil at 2400 mg/m2, repeated every 2 weeks). Granulocyte colony-stimulating factor was allowed for those who suffered grade 3 or 4 neutropenia. The treatment was continued for 12 cycles unless the patient had progressive disease (PD), stable disease (SD) with symptom deterioration, unacceptable adverse events, or requested to terminate the treatment prematurely.
Study design
The sample size was estimated by the Simon’s two-stage design. The expected ORR for the modified FOLFIRINOX was initially assumed to be 30%. If the ORR was less than 10%, the modified FOLFIRINOX was considered to be ineffective. Due to the possible occurrence of the first type of error (α = 0.05) and the possible occurrence of the second type of error (β = 0.10), 18 patients were needed in the first stage of the study. If more than 2 patients were responsive to the treatment, the second stage would be initiated, and 17 more patients would be enrolled. Considering a withdrawal rate of 15%, a total of 40 patients were needed in this study.
Evaluation of response
Patients completing at least one cycle of the modified FOLFIRINOX with at least one follow-up tumor assessment were considered evaluable for response. Computed tomography (CT) of the chest, abdomen, and pelvic cavity was repeated every 4 cycles. The treatment response was determined in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.0) by the investigators. Adverse events were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE, version 4.0) on days 1, 8, 15 of the treatment cycle. Second-line treatment was strongly recommended for those who were still with good performance status after PD was observed during the treatment period.
Study endpoints
The primary endpoint of this phase II trial was ORR, and the secondary endpoints were disease control rate (DCR), OS, PFS and the rates of adverse events. ORR was determined as the percentage of patients who had a complete (CR) or partial response (PR). DCR was defined as the percentage of patients who had a CR, PR, or SD. In addition, OS was calculated from the date of enrollment to death from any cause. PFS was defined as the time interval from recruitment until radiological or clinical progression or death from any cause.
Follow-up
All patients received regular blood tests including tumor markers detection and CT scans of the chest, abdomen, and pelvic cavity every 2 months unless they had PD. Patients with PD after modified FOLFIRINOX treatment were followed-up every 3 months by telephone until death. The end of follow-up period was December 20, 2018.
Statistical analysis
Descriptive statistical analysis was used to determine the ORR and DCR. The OS and PFS were estimated using the Kaplan–Meier method. Log-rank test was used for statistical comparisons between survival curves. All statistical analyses were carried out using the SPSS software, version 22.0 (SPSS Inc., Chicago, IL, USA). A two-sided P value of less than 0.05 was considered significant.