DISCUSSION
nausea, myalgia, neutropenia, fatigue, nab‐paclitaxel, infections, occult unresectable, node‐positive pancreatic adenocarcinoma, pancreatic cancer, nab‐paclitaxel‐based, Anderson Cancer, unresectable disease
DISEASE PROGRESSION, METASTASIS, NEUTROPENIA, ADVERSE EVENTS, INFECTIONS, METASTATIC DISEASE, PANCREATIC CANCER
We found that neoadjuvant therapy with nab‐paclitaxel and gemcitabine followed by long‐course chemoradiation with fluoropyrimidine is feasible for patients with borderline resectable and clinically node‐positive pancreatic adenocarcinoma, with a R0 resection of 42% among all 19 participants and a pathologic near‐complete response of 18% among the 11 resection specimens. While both radiographic and pathologic responses were observed from neoadjuvant treatment with chemotherapy and radiation, there is still a high proportion of patients who experienced local and/or metastatic disease progression, some of which resulted in clinical deterioration, prior to or soon after surgical resection. Chemotherapy‐related adverse events such as neutropenia, nausea, fatigue, myalgia, and infections were similar to what is reported in respective package inserts. The population in this study was particularly high risk with 53% of patients having both arterial and venous vascular involvement, thus potentially influencing the number of patients who were ultimately able to undergo resection. Our experience also highlighted the importance of strict evaluation criteria in future studies, such as baseline diagnostic laparoscopy and dedicated CT pancreas protocol to rule out metastatic and unresectable disease that may have been present at baseline.Several studies have compared neoadjuvant gemcitabine with nab‐paclitaxel to FOLFIRINOX chemotherapy. First, a retrospective cohort of 485 patients at MD Anderson Cancer Center showed that these two neoadjuvant regimens had similar overall survival despite higher resection rates with FOLFIRINOX.R0 resection is commonly chosen as the primary endpoint among neoadjuvant trials for pancreatic cancer, but such outcomes vary widely among reported trials. A recent analysis from Medical College of Wisconsin showed that when neoadjuvant therapy is specifically given to patients with borderline resectable pancreatic cancer, the expected resection rate is approximately 62% (115 among 185 patients), with final R0 resection rate of 60% (In the future, pancreatic cancer subtyping by detailed gene expression panels may be able to measure differing responses to chemotherapy and develop clinically relevant blood‐based markers and biopsy‐based markers during a course of neoadjuvant therapy.Several limitations were noted in our study. First, this phase 2 clinical trial which ended prematurely after multidisciplinary review and discussion with the sponsor, and so it did not enroll the intended 44 patients despite meeting interim analysis criteria to continue. Larger trials with randomized design will be needed to confirm efficacy endpoints. Second, diagnostic laparoscopy and dedicated pancreas CT protocol were not required in the original study design, which may have contributed to the lower‐than‐expected resection numbers by possibly including those with occult unresectable and metastatic disease. Third, our neoadjuvant chemotherapy duration of only 2 months of gemcitabine and nab‐paclitaxel is relatively short compared with other contemporary neoadjuvant trials, some of which mandated 4 months of neoadjuvant chemotherapy.Overall, neoadjuvant therapy with nab‐paclitaxel and gemcitabine along with chemoradiation provides an acceptable R0 resection rate compared with other preoperative treatment regimens. The high risk of distant metastasis in pancreatic cancer highlights the need for detailed baseline workup as well as early, extended multiagent preoperative chemotherapy prior to resection. Several ongoing clinical trials in the Stage 4 setting may identify other neoadjuvant therapy candidates (liposomal irinotecan, NCT04233866; immunotherapy checkpoint inhibitor, NCT03193190). Additionally, an adaptive strategy based on radiographic and blood‐based assessments, recently activated at our institution, could yield optimal clinical outcomes in potentially resectable patients receiving neoadjuvant therapies (NeoOPTIMIZE, NCT04539808). Therefore, preoperative gemcitabine and nab‐paclitaxel‐based chemotherapy, perhaps of longer duration than two cycles, followed by chemoradiation represents a feasible, alternate strategy to FOLFIRINOX‐based therapy for borderline resectable pancreatic cancer, especially for those patients not felt to be candidates for more intensive regimens. Ultimately, both regimens could be personalized for future patients with potentially resectable pancreatic cancer.