Neoadjuvant therapy does not alter pattern of progression in pancreatic adenocarcinoma

Abstract

Background: Neoadjuvant therapy (NAT) has been accepted as a strategy to treat borderline resectable and locally-advanced pancreatic adenocarcinoma (PDAC). FOLFIRINOX in addition to radiation therapy allows selected patients the opportunity to undergo a potentially curative operation, with a high rate of margin-negative resection. Given that the vast majority of PDAC patients that undergo curative treatment either recur or develop distant metastases, we sought to evaluate if NAT leads to changes in patterns of progression. Methods: Using the MGH prospectively maintained PDAC database we identified patients with resectable PDAC. First site of progression was designated as either locoregional (LR) or as distant metastasis (DM). DM included metastases to liver, lung, peritoneum, or other sites. If both LR and DM were identified on imaging, patients were categorized as DM. Patients with resectable disease were treated with upfront resection, adjuvant chemotherapy, and individualized radiotherapy. In order to understand if NAT in borderline resectable patients led to a difference in site of first progression compared to resectable disease, we investigated patients from the MGH Phase-II trial evaluating total neoadjuvant therapy (TNT) in borderline-resectable PDAC (Murphy et al. Jama Oncol, 2018), in which site of first progression was collected prospectively. P-value < 0.05 was considered significant. Results: Using the MGH PDAC database from 2011 to 2017, 99 resectable patients progressed during a median follow-up of 60.1 months. The median disease-free survival (mDFS) in this group was 13.0 months. The median overall survival (mOS)was 23.4 months. Patients with resectable PDAC were treated with adjuvant chemotherapy (100%) and radiation (35.5%). Margin-negative resection was achieved in 77 of 99 patients (77.8%). In resectable patients, site of first progression was found to be LR in 18.2% of patients and was DM in 81.8% of patients. We compared resectable patients to patients from the MGH Phase-II trial (NCT01591733) evaluating TNT in borderline resectable PDAC. Out of 48 evaluable patients, 36 recurred during the median follow-up period of 36 months. The mDFS was 17.7 months and the mOS was 37.7 months. All patients in this trial received neoadjuvant chemotherapy with FOLIFIRINOX, followed by chemoradiation. 31 of 48 patients (65%) achieved an R0 resection. Out of these patients, 50% had site of first progression locoregionally and 50% had site of first progression as DM. The distribution of site of first progression was different between the two cohorts (p < 0.0001) and demonstrated an increase in the early failure of locoregional control in patients with borderline resectable PDAC treated with NAT. Conclusion: Upfront resectable patients with PDAC who progress after curative-intent resection and adjuvant therapy do so more often distantly than locoregionally. However, in patients with borderline resectable PDAC treated with neoadjuvant chemotherapy and radiation, there is an increase in local failure as site of first progression, versus distant control in comparison to resectable patients treated with adjuvant therapy. This may be a reflection of altered disease biology between borderline and resectable patients, or better distant control with NAT.