Predictors of Resectability and Survival in Patients With Borderline and Locally Advanced Pancreatic Cancer who Underwent Neoadjuvant Treatment With FOLFIRINOX.

OBJECTIVE: The aim of this study was to determine (1) whether preoperative factors can predict resectability of borderline resectable (BR) and locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant FOLFIRINOX, (2) which patients might benefit from adjuvant therapy, and (3) survival differences between resected BR/LA patients who received neoadjuvant FOLFIRINOX and upfront resected patients. BACKGROUND: Patients with BR/LA PDAC are often treated with FOLFIRINOX to obtain a margin-negative resection, yet selection of patients for resection remains challenging. METHODS: Clinicopathologic data of PDAC patients surgically explored between 04/2011-11/2016 in a single institution were retrospectively collected. RESULTS: Following neoadjuvant FOLFIRINOX, 141 patients were surgically explored (BR: 49%, LA: 51%) and 110 (78%) were resected. Resected patients had lower preoperative CA 19-9 levels (21 vs 40 U/mL, P = 0.03) and smaller tumors on preoperative computed tomography (CT) scan (2.3 vs 3.0 cm, P = 0.03), but no predictors of resectability were identified. Median overall survival (OS) was 34.2 months from diagnosis for all FOLFIRINOX patients and 37.7 months for resected patients. Among resected patients, preoperative CA 19-9 >100 U/mL and >8 months between diagnosis and surgery predicted a shorter postoperative disease-free survival (DFS); Charlson comorbidity index >1, preoperative CA 19-9 >100 U/mL and tumor size (>3.0 cm on CT or >2.5 cm on pathology) predicted decreased OS. DFS and OS were significantly better for BR/LA PDAC patients treated with neoadjuvant FOLFIRINOX compared with upfront resected patients (DFS: 29.1 vs 13.7, P < 0.001; OS: 37.7 vs 25.1 months from diagnosis, P = 0.01). CONCLUSION: BR/LA PDAC patients with no progression on neoadjuvant FOLFIRINOX should be offered surgical exploration. Except size, traditional pathological parameters fail to predict survival among resected FOLFIRINOX patients. Resected FOLFIRINOX patients have survival that appears to be superior than that of resectable patients who go directly to surgery.

NCCN Guidelines Insights: Neuroendocrine and Adrenal Tumors, Version 2.2018.

The NCCN Guidelines for Neuroendocrine and Adrenal Tumors provide recommendations for the management of adult patients with neuroendocrine tumors (NETs), adrenal gland tumors, pheochromocytomas, and paragangliomas. Management of NETs relies heavily on the site of the primary NET. These NCCN Guidelines Insights summarize the management options and the 2018 updates to the guidelines for locoregional advanced disease, and/or distant metastasis originating from gastrointestinal tract, bronchopulmonary, and thymus primary NETs.

Intraoperative Radiotherapy in the Era of Intensive Neoadjuvant Chemotherapy and Chemoradiotherapy for Pancreatic Adenocarcinoma.

OBJECTIVES: Improved outcomes with FOLFIRINOX or gemcitabine with nab-paclitaxel in the treatment of metastatic pancreatic adenocarcinoma (PDAC) have prompted incorporation of these regimens into neoadjuvant treatment of locally advanced unresectable PDAC. Whereas some patients remain unresectable on surgical exploration, others are able to undergo resection after intensive neoadjuvant treatment. We evaluated outcomes and toxicity associated with use of intensive neoadjuvant treatment followed by intraoperative radiotherapy (IORT) in combination with resection or exploratory laparotomy. METHODS: We retrospectively analyzed patients with locally advanced unresectable or borderline-resectable PDAC who received intensive neoadjuvant treatment with induction chemotherapy and chemoradiotherapy followed by exploratory laparotomy in an IORT-equipped operating suite between 2010 and 2015. Surgical outcomes and overall survival (OS) were compared. RESULTS: Of 68 patients, 41 (60.3%) underwent resection, 18 (26.5%) had unresectable disease, and 9 (13.2%) had distant metastases. Of 41 resectable patients, 22 received IORT for close/positive resection margins on intraoperative frozen section. There was no significant difference in operative times or morbidity with addition of IORT to resection. Median OS was 26.6 months for all patients who underwent resection, 35.1 months for patients who underwent resection and IORT, and 24.5 months for patients who underwent resection alone (P=NS). Of 18 patients with unresectable disease, all but 1 received IORT, with median OS of 24.8 months. IORT was associated with increased hospital stay (4 vs. 3.5 d), but no significant difference in operative times or morbidity. CONCLUSIONS: IORT in addition to intensive neoadjuvant chemotherapy and chemoradiotherapy was not associated with increased toxicity when used with resection or exploratory laparotomy, and was associated with encouraging survival rates in patients with close/positive margins and patients with unresectable disease.

A phase 1/2 and biomarker study of preoperative short course chemoradiation with proton beam therapy and capecitabine followed by early surgery for resectable pancreatic ductal adenocarcinoma.

PURPOSE: To evaluate the safety, efficacy and biomarkers of short-course proton beam radiation and capecitabine, followed by pancreaticoduodenectomy in a phase 1/2 study in pancreatic ductal adenocarcinoma (PDAC) patients. METHODS AND MATERIALS: Patients with radiographically resectable, biopsy-proven PDAC were treated with neoadjuvant short-course (2-week) proton-based radiation with capecitabine, followed by surgery and adjuvant gemcitabine. The primary objective was to demonstrate a rate of toxicity grade ≥ 3 of <20%. Exploratory biomarker studies were performed using surgical specimen tissues and peripheral blood. RESULTS: The phase 2 dose was established at 5 daily doses of 5 GyE. Fifty patients were enrolled, of whom 35 patients were treated in the phase 2 portion. There were no grade 4 or 5 toxicities, and only 2 of 35 patients (4.1%) experienced a grade 3 toxicity event (chest wall pain grade 1, colitis grade 1). Of 48 patients eligible for analysis, 37 underwent pancreaticoduodenectomy. Thirty of 37 (81%) had positive nodes. Locoregional failure occurred in 6 of 37 resected patients (16.2%), and distant recurrence occurred in 35 of 48 patients (72.9%). With median follow-up of 38 months, the median progression-free survival for the entire group was 10 months, and overall survival was 17 months. Biomarker studies showed significant associations between worse survival outcomes and the KRAS point mutation change from glycine to aspartic acid at position 12, stromal CXCR7 expression, and circulating biomarkers CEA, CA19-9, and HGF (all, P<.05). CONCLUSIONS: This study met the primary endpoint by showing a rate of 4.1% grade 3 toxicity for neoadjuvant short-course proton-based chemoradiation. Treatment was associated with favorable local control. In exploratory analyses, KRAS(G12D) status and high CXCR7 expression and circulating CEA, CA19-9, and HGF levels were associated with poor survival.

Pancreatic neuroendocrine tumors with involved surgical margins: prognostic factors and the role of adjuvant radiotherapy.

PURPOSE: Pancreatic neuroendocrine tumors (pNET) are rare neoplasms associated with poor outcomes without resection, and involved surgical margins are associated with a worse prognosis. The role of adjuvant radiotherapy (RT) in these patients has not been characterized. METHODS AND MATERIALS: We retrospectively evaluated 46 consecutive patients with positive or close (<1 mm) margins after pNET resection, treated from 1983 to 2010, 16 of whom received adjuvant RT. Median RT dose was 50.4 Gy in 1.8-Gy fractions; half the patients received concurrent chemotherapy with 5-fluorouracil or capecitabine. No patients received adjuvant chemotherapy. Cox multivariate analysis (MVA) was used to analyze factors associated with overall survival (OS). RESULTS: Median age at diagnosis was 56 years, and 52% of patients were female. Median tumor size was 38 mm, 57% of patients were node-positive, and 11% had a resected solitary liver metastasis. Patients who received RT were more likely to have larger tumors (median, 54 mm vs. 30 mm, respectively, p = 0.002) and node positivity (81% vs. 33%, respectively, p = 0.002) than those not receiving RT. Median follow-up was 39 months. Actuarial 5-year OS was 62% (95% confidence interval [CI], 41%-77%). In the group that did not receive RT, 3 patients (10%) experienced local recurrence (LR) and 5 patients (18%) developed new distant metastases, while in the RT group, 1 patient (6%) experienced LR and 5 patients (38%) developed distant metastases. Of all recurrences, 29% were LR. On MVA, male gender (adjusted hazard ratio [AHR] = 3.81; 95% CI, 1.21-11.92; p = 0.02) and increasing tumor size (AHR = 1.02; 95% CI, 1.01-1.04; p = 0.007) were associated with decreased OS. CONCLUSIONS: Long-term survival is common among patients with involved-margin pNET. Despite significantly worse pathologic features among patients receiving adjuvant RT, rates of LR between groups were similar, suggesting that RT might aid local control, and merits further evaluation.