We performed a retrospective analysis at the University of Miami Sylvester Comprehensive Cancer Center and Jackson Memorial Hospital in Miami, Florida of all patients with LAPC who received first-line treatment with FOLFIRINOX. Patients were identified by searching the pancreatic cancer database which was approved by the University of Miami Institutional Review Board (IRB). This IRB-approved database provided a waiver of the requirement for informed consent for retrospective studies and allowed for publication of de-identified data.
The medical, radiation and surgical oncologists in the group developed an algorithm for uniform treatment of this group of patients as follows. Patients were selected for treatment with FOLFIRINOX if they had a histological or cytological diagnosis of pancreatic adenocarcinoma, an Eastern Cooperative Group performance status (ECOG PS) of 0 or 1, adequate organ function, and UR/BR LAPC. For patients who presented with biliary obstruction, adequate biliary drainage was required prior to initiation of this chemotherapy. The determination of resectability was made by multidisciplinary review. Since there is currently no internationally agreed-upon definition of borderline-resectable LAPC, we applied the American Hepato-Pancreato-Biliary Association/Society of Surgical Oncology/Society for Surgery of the Alimentary Tract (AHPBA/SSO/SSAT) criteria [2
]. These criteria are summarized in Table
. The data used to determine resectability included pretreatment contrast-enhanced CT scans (CECT's) and endoscopic ultrasound (EUS) in all patients and surgical exploration when available.
Criteria used for determining resectability for non-metastatic pancreatic cancer
Treatment with FOLFIRINOX proceeded with doses identical to the ACCORD-11 trial [4
]. On day 1 of every 14-day cycle, oxaliplatin was administered at a dose of 85
mg per square meter, irinotecan at 180
mg per square meter, folinic acid at 400
mg per square meter, and 5-fluoruracil (5-FU) as a bolus of 400
mg per square meter. 5-FU was then administered as a continuous infusion of 2400
mg per square meter over 46 hours. Filgrastim was at the discretion of the treating physician. Treatment continued until progression of disease, intolerable toxicity or maximum response. Toxicities were assessed at every fortnightly visit and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4 [9
]. Criteria for dose modification were similar to those described in the ACCORD-11 trial. Response assessment by CECT's were performed every 8
weeks on therapy or sooner if progression was suspected by symptoms or rising CA19-9.
After every CECT scan during treatment, each patient’s case was reviewed at a multidisciplinary conference to determine whether the reason for defining the patient as UR or BR had improved. Since size was not the only criteria used in this evaluation, traditional response criteria (such as RECIST) were not employed. For example, if a tumor was categorized as BR due to abutment of the SMA up to 180°, the extent of abutment was re-evaluated after every scan to determine if this was improving and if the patient would now be a surgical candidate. If two consecutive scans during treatment showed similar findings with no improvement, this was considered to be the maximum response. Maximum tolerability was defined as the point when excessive toxicities warranted stopping FOLFIRINOX, even if a patient had not achieved their maximum response. Because we used an algorithm of real-time monitoring of response and toxicity, there was no predefined minimum or maximum number of cycles.
At maximum response or tolerability, patients who appeared to be resectable by imaging criteria were offered surgical exploration and resection (within 6-8
weeks after chemotherapy) followed by postoperative CCRT. Patients who remained unresectable at maximum response or tolerability of FOLFIRINOX were offered CCRT. For radiation sensitization, patients received concurrent gemcitabine at 600
mg per square meter per week. Intensity-modulated radiation therapy (IMRT) was delivered in a standard fashion to a total dose of 50.4
Gy in 28 fractions. At the end of CCRT, patients were re-evaluated with CECT's to determine resectability. Post-CCRT treatment was left to the discretion of the treating physicians.
The primary endpoint for this analysis was the R0 resection rate. An R0 resection was defined as at least 1
mm free margins. An R1 resection was defined as tumor within 1
mm from the closest margin. Secondary endpoints included safety, tolerability, overall survival and progression-free survival. All patients who received at least one cycle of FOLFIRINOX were included in the analysis. PFS and OS were calculated as follows; PFS was defined as the duration in months from the date of the first cycle of FOLFIRINOX until the date of documented progression, recurrence or death, whichever was sooner. OS was defined as the duration in months from the date of the first cycle of FOLFIRINOX until the date of death from any cause. Patients known to be alive were censored at the time of last contact. PFS and OS were estimated by the Kaplan–Meier method with corresponding two-sided 95
% CI's for survival proportions based on Greenwood's variance and the log-transform method [10
]. Descriptive statistics were also used to summarize data.