DISSECTING THE ROLE OF NODAL METASTASES LOCATION IN PANCREATODUODENECTOMY AFTER NEOADJUVANT TREATMENT FOR CANCER: RESULTS FROM A PROSPECTIVE LYMPHADENECTOMY PROTOCOL

Importance: Guidelines recommend surgical exploration in selected patients with locally advanced pancreatic cancer (LAPC) following induction chemotherapy. However, surgical exploration, has potential drawbacks related to surgical risks and treatment breaks, which apply in particular to patients undergoing exploration without resection (i.e. non-therapeutic laparotomy). Data regarding the impact of non-therapeutic laparotomy for LAPC treated with (m)FOLFIRINOX induction chemotherapy could guide aggresiveness of surgeons for this patient population.
Objective: To assess the incidence and oncologic impact of a non-therapeutic laparotomy for LAPC treated with (m)FOLFIRINOX induction chemotherapy.
Design: Retrospective cohort study
Setting: International multicenter study including patients from 5 referral centers in the USA and The Netherlands (2012-2019).
Participants: Patients diagnosed with pathology-proven LAPC treated with ≥1 cycle (m)FOLFIRINOX (± radiotherapy). Patients with metastatic disease on radiologic (re)staging or clinical deterioration during induction therapy were excluded. Patients undergoing non-therapeutic laparotomy (group A) were compared to those not explored (group B). Patients undergoing resection were assigned to group C.
Main outcomes and measures: 90-day mortality, palliative systemic treatment, and median OS from date of pathology-proven diagnosis.
Results: Overall, 663 patients with LAPC were included, of whom 78 (11.8%) subsequently received a second-line induction chemotherapy after (m)FOLFIRINOX and 413 (66.8%) received radiotherapy. In total, 67 patients (10.1%) were included in group A, 425 patients (64.1%) in group B, and 171 patients (25.8%) in group C. Resection was aborted in 28.2% (n=67/238) of all surgical explorations, commonly due to occult metastases (n=30/238, 12.6%). The 90-day mortality in group A was 3.0% (n=2/67). The proportion of patients receiving palliative therapy did not differ between groups A and B (65.9% vs. 73.1%; P=0.307). Median OS for groups A and B were 20.4 (95%CI; 15.9-27.3) and 20.2 (95%CI; 19.1-22.7) months respectively (P=0.752). Median OS in group C was 36.1 (95%CI; 30.5-41.2) months. Corresponding 3-year survival rates for all groups were 25.0%, 21.4% and 51.1%, respectively. Compared to unexplored patients, non-therapeutic laparotomy was not associated with reduced OS (HR=0.88 [95%CI 0.61-1.27]) in Cox regression analysis.
Conclusion and relevance: Even in experienced hands, about ¼ of surgically explored LAPC patient will remain unresectable. However, non-therapeutic laparotomy does not appear to substantially reduce short- and long-term outcomes compared to similar patients who are not explored.

Introduction
The role of lymph node (LN) parameters in pancreatoduodenectomy (PD) for cancer has been mainly investigated in the upfront surgery setting. Yet, due to the impact of neoadjuvant therapy (NAT) on nodal status, these results cannot be directly translated to post-NAT PD. This study aimed to examine LN yields and metastases per anatomical stations and how the extension of LN dissection affects nodal staging in post-NAT PD. Lastly, the prognostic role of LN parameters was investigated.
Methods
An institutional lymphadenectomy protocol was prospectively applied to all post-NAT PDs from June 2013. Lymphadenectomy included stations 5/6/8a-p/12a-b-c-p/13/14a-b/17 and jejunal mesentery LNs. Stations embedded in the PD specimen (13/14/17/jejunal) were defined as first-echelon, those sampled separately (5/6/8/12) as second-echelon. The prognostic impact of LN parameters in N+ patients was evaluated using uni- and multivariable Cox regression. To avoid collinearity, separate multivariable models were designed for each nodal parameter.
Results
Among 288 patients 61% received FOLFIRINOX, 30% Gem-Abraxane. The median number of examined (ELN) and positive LNs (PLN) were 43 and 1, and 185 patients were N+ (64%). The commonest metastatic sites were stations 13 (51%), 14 (34%) and 17 (32%). The overall rates of first and second echelon involvement were 60% and 20%. The median number of ELN and PLN in the first echelon were 29 and 1. The addition of second echelon LNs increased nodal counts by 9 ELN and 0 PLN, resulting in only minor changes in staging.
The median follow-up was 25.1 months, 35.8 in censored cases. At multivariable analysis, second echelon involvement, ≥4 metastatic stations, metastases to station 8 and jejunal mesentery LNs, but not N2 status, were independently associated with survival of N+ patients, along with adjuvant treatment.
The median recurrence-free survival (RFS) was 14.8 months and 176 patients experienced recurrence (71%), among which 41 were local relapses (23%). In N+ patients, nodal echelons, ≥4 metastatic stations and tumor involvement of station 8,14 and jejunal mesentery LNs were independent predictors of RFS, along with Ca 19.9 response, T- and R-status and adjuvant treatment. Distant recurrences incrementally increased with nodal involvement (Figure).
Conclusion
LN metastases most commonly occur in first-echelon LNs, and first-echelon dissection provides an adequate number of ELN for optimal staging. Examining second-echelon LNs does not improve the staging process substantially. Yet, second-echelon involvement is prognostically relevant, as well as metastases to station 8 and jejunal mesentery LNs. These data have potential implications when assessing surgical indication after NAT. Moreover, intraoperative frozen section of station 8 might help decision-making, especially in technically demanding cases or fragile patients.