Neoadjuvant Nab-paclitaxel and Gemcitabine in Borderline Resectable or Locally Advanced Unresectable Pancreatic Adenocarcinoma in Patients Who Are Ineligible for FOLFIRINOX

Patients and Methods

A retrospective analysis was performed at the University of Kentucky Markey Cancer Center in Lexington, Kentucky and the University of Miami, Sylvester Cancer Center, Miami, FL of all patients with BRPC or LAPC who received first-line treatment with AG. Patients were identified by searching the pancreatic cancer database which was approved by the Institutional Review Board (IRB) of both institutions.

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 AG if they had a histological or cytological diagnosis of pancreatic adenocarcinoma, an Eastern Cooperative Group performance status (ECOG PS) of 0-3, adequate organ function, BRPC or LAPC, or deemed ineligible for FOLFIRINOX neoadjuvant therapy. The decision about ineligibility for FOLFIRINOX was based on the judgement of the treating medical oncologist and usually was because of advanced age, poor performance status (PS) or significant medical comorbidities. For patients who presented with biliary obstruction, adequate biliary drainage was required prior to initiation of this chemotherapy. The radiographic determination of resectability was made by standardized multidisciplinary review. The NCCN (National Comprehensive Cancer Network) criteria for resectability were applied (9). The data used to determine resectability included pretreatment contrast-enhanced CT scans (CECT's) and endoscopic ultrasound (EUS) in all patients.

The treatment regimen was the same as published in the MPACT trial for metastatic PDAC (7). This consisted of gemcitabine 1,000 mg/m² and nab-paclitaxel 125 mg/m² administered on days 1, 8 and 15 every 28 days for at least 2-4 cycles. Treatment continued until progression of disease, intolerable toxicity or maximum response. Toxicities were assessed at every visit and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4. Criteria for dose modification were similar to those described in the MPACT trial. Response assessment by CECT's were performed every 8 weeks on therapy or sooner if progression was suspected by symptoms or rising serum 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 BRPC or UR LAPC had improved. Since size was not the only criterium used in this evaluation, traditional response criteria (such as RECIST) were not employed. 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 AG, even if a patient had not achieved their maximum response. Because an algorithm of real-time monitoring of response and toxicity was used, there was no predefined minimum or maximum number of cycles.

At maximum response or maximum 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 chemoradiation. Patients who remained UR at maximum response or tolerability of AG were offered chemoradiation. For radiation sensitization, patients received concurrent capecitabine. Intensity-modulated radiation therapy (IMRT) was delivered in a standard fashion to a total dose of 50.4 Gy in 28 fractions or 52.5 Gy in 25 fractions. At the end of chemoradiation, patients were re-evaluated with CECT's to determine resectability. Post-CCRT treatment was left to the discretion of the treating physicians. Dose intensity was defined as the percentage of the full dose that was delivered.

The primary endpoint for this analysis was R0 resection rate. Secondary endpoints included Overall survival (OS), progression free survival (PFS), response rate, and toxicity. An R0 resection was defined as at least 1 mm free margins. Patients known to be alive were censored at the time of last contact. All patients who received at least one cycle of AG were included in the analysis. PFS was defined as the duration in months from the date of the first cycle of AG until the date of documented progression, recurrence, or death, whichever was soonest. OS and PFS were estimated by the Kaplan–Meier method with corresponding two-sided 95% confidence interval (CI) for survival proportions based on Greenwood's variance and the log-transform method. Statistical significance was defined as p<0.05, and all tests were two-sided. Tests were performed using the IBM SPSS statistics software version 24 (IBM, NY, USA).