HEPATECTOMY BEFORE PRIMARY TUMOR RESECTION AS PREFERRED APPROACH FOR SYNCHRONOUS LIVER METASTASES FROM RECTAL CANCER

Background

Long-term survival in patients with localized pancreatic adenocarcinoma (PDAC) or ampullary adenocarcinoma (AA) who undergo resection is rare, even in lymph node (LN)-negative disease. We aimed to assess the frequency of occult metastases (OM) in patients with resected PDAC or AA discovered with a detailed pathologic examination technique on LNs previously considered negative with conventional analysis. We also examined the association between OM and overall survival (OS).

Methods

Patients with LN-negative disease on conventional pathologic analysis following resection of PDAC or AA from 2010 to 2020 were identified from our institutional database, and those with available tissue for re-analysis were included. LNs were selected for re-examination based on proximity to the tumor and size. Original hematoxylin & eosin slides, three 4-micron-thick sections from deeper levels, and one pan-cytokeratin (AE1/AE3/PCK26) immunostain were examined for each block. The primary outcome was the frequency of OM. The secondary outcome was OS.

Results

A total of 598 LNs from 74 LN-negative patients (PDAC=71; AA=3) were re-examined in detail. A total of 49 patients (66.2%) underwent pancreatoduodenectomy, 17 (23.0%) underwent distal pancreatectomy/splenectomy, and 7 (10.8%) underwent total pancreatectomy. The median LN yield was 19. Sixteen patients (21.6%) had positive surgical margins, 18 (24.3%) had lymphovascular invasion, and 47 (63.5%) had perineural invasion. Twenty-six patients (35.1%) received neoadjuvant therapy and 35 (47.3%) received adjuvant chemotherapy.
On detailed LN analysis, 19 patients (25.7%) had OM. Of these, 9 OM (47.4%) were found only with immunohistochemistry but not on hematoxylin & eosin staining. The number of positive lymph nodes ranged from 1-3. On multivariable analysis, no clinicodemographic or pathologic factors were associated with OM.
The proportion of OM was 10.5% for patients with operative LN yields of <10 LNs, 42.0% for 10-19 LNs, 37.0% for 20-29 LNs, and 10.5% for ≥30 LNs. On conventional pathologic analysis, 3 patients (15.8%) had stage IA disease, 9 patients (26.5%) had stage IB disease, and 7 patients (36.8%) had stage IIA disease, all upstaged to stage IIB on detailed LN analysis.
On survival analysis, patients with OM had an associated decrease in OS as compared to those without OM (median OS: 22.3 vs. 50.5 months; HR=3.86, 95% CI: 1.53-9.78; Figure).

Conclusions

There is a high discordance rate between conventional and detailed LN pathologic analysis in resected PDAC and AA. The presence of OM is associated with worse OS. The high rate of occult nodal disease may in part explain poor survival outcomes in patients with node-negative disease.

BACKGROUND:
Post-pancreatoduodenectomy patients at our institution are managed on risk-stratified pancreatectomy care pathways preoperatively determined by risk of clinically relevant postoperative pancreatic fistula (CR-POPF). We previously published cut-off ranges for drain fluid amylase on postoperative day (POD) 1 (DFA1) and POD 3 (DFA 3) to encourage timely drain removal. The aim of this study was to validate and recalibrate our cut-off values using a prospective cohort of patients managed immediately after implementing those DFA thresholds.

METHODS:
We performed a single-institution prospective cohort study of consecutive patients who underwent pancreatoduodenectomy from DFA1/DFA3 threshold implementation in February 2019 to April 2022. Ninety-day postoperative complications were prospectively graded and reported according to the ACCORDION system and International Study Group on Pancreatic Surgery definitions. Patient characteristics, perioperative details, and DFA1/DFA3 (measured in U/L) were compared between care pathways. Receiver Operating Characteristic (ROC) curve analysis was performed to determine optimal cut-off values based on preoperative risk stratification.

RESULTS:
In total, 267 patients underwent 228 (85%) open and 39 (15%) robotic procedures, with 173 (65%) patients stratified into low-risk and 94 (35%) into high-risk pathways. Seven (4%) low-risk patients and 21 (22%) high-risk patients developed CR-POPF. Of 147 patients with drains removed before/on POD3, only 1 (0.7%) developed CR-POPF in the prospective cohort recalibration. CR-POPF was excluded with 100% sensitivity if DFA1 <286 (area under curve, AUC=0.893, p=0.001) or DFA3 <97 (AUC=0.856, p=0.002) in low-risk patients. DFA1 <137 (AUC=0.786, p<0.001) or DFA3 <56 (AUC=0.819, p<0.001) were 100% sensitive in ruling out CR-POPF in high-risk patients. Our previous DFA1 cut-offs of 100 in low-risk patients and <26 in high-risk patients were 100% sensitive, while our DFA3 cut-offs of 300 (low-risk) and 200 (high-risk) had 57% and 91% sensitivity.

CONCLUSION:
Risk-stratified post-pancreatoduodenectomy DFA thresholds can effectively and safely guide early POD1/POD3 drain removal. Previously identified cut-off values appear overly restrictive for DFA1 and overly liberal for DFA3. As a learning health system, we further propose recalibrating our drain removal thresholds to DFA1 ≤300, DFA3 ≤100 in low-risk patients and DFA1 ≤100, DFA3 ≤50 in high-risk patients. This methodology can be implemented at other centers to develop institution-specific criteria for early drain removal.

Introduction: There is a paucity of evidence supporting the use of adjuvant radiation therapy in resected biliary cancer. National guidelines recommend the consideration of use in patients with positive margins after resection, however, supporting evidence comes mainly from a phase II trial of 79 patients, SWOG S0809, which demonstrated that the use of adjuvant chemoradiation was well tolerated and resulted in an overall median survival of 35 months. We aimed to use a large national database to evaluate the use of adjuvant chemoradiation in resected extrahepatic bile duct and gallbladder cancer.

Methods: Using the National Cancer Database (NCDB), we selected patients from 2004-2017 with pT2-4, pN0-1, M0 extrahepatic bile duct or gallbladder adenocarcinoma with either R0 or R1 resection margins, and examined factors associated with overall survival using Cox proportional hazards model. We also examined overall survival in a subset of patients who received adjuvant chemo- and radiotherapy (CRT) using the Kaplan-Meier method and log rank test.

Results: Overall, 4,997 patients with gallbladder or extrahepatic adenocarcinoma with available survival information meeting the SWOG S0809 criteria were selected from the NCDB, 469 of whom received both adjuvant chemo- and radiotherapy. Of the CRT cohort, all patients received multi-agent chemotherapy, 211 (45.0%) had extrahepatic cholangiocarcinoma and 258 (55.0%) had gallbladder cancer, the majority were pT3 (n=281, 59.9%), pN1 (n=323, 68.9%), and had an R0 resection (n=387, 82.5%). Median overall survival in patients undergoing CRT was 36.9 months, and was not different between primary sites (p=0.841). Patients with a R1 margin had abbreviated overall survival compared to patients with an R0 resection (41.8 months vs 24.1 months, p<0.001). On multivariable cox regression analysis of all patients who underwent resection agnostic to adjuvant therapy, age, insurance status, Charlson-Deyo comorbidity index, T-stage, N-stage, lymphovascular invasion, margin status, chemo- and radiotherapy were all associated with overall survival. Adjuvant chemoradiation compared to chemotherapy alone showed an overall survival benefit for patients with either R0 (41.8 vs 30.8 months, p<0.001) or R1 (24.1 vs 20.2 months, p<0.001) resections.

Conclusion: Using a large national database, our data validates the findings of SWOG S0809 with a similar median overall survival in patients receiving chemoradiation. Patients receiving CRT had improved overall survival compared to patients receiving chemotherapy only after both R0 and R1 resections. These data further support the consideration of adjuvant multi-modal therapy in resected biliary cancers, regardless of margin status.

Background: For patients with synchronous liver metastases (LM) from rectal cancer, consensus on surgical sequencing is lacking. We compared outcomes between the reverse (hepatectomy first), classic (primary tumor resection first), and combined (simultaneous hepatectomy and primary tumor resection) approaches.
Methods: A prospectively maintained database was queried for patients with rectal cancer LM diagnosed before primary tumor resection who underwent hepatectomy for LM from January 2004 to April 2021. Clinicopathological factors and survival were compared between the three approaches.
Results: Among 274 patients, 141 (51%) underwent the reverse approach; 73 (27%), the classic approach; and 60 (22%), the combined approach. Higher carcinoembryonic antigen level at LM diagnosis and higher number of LM were associated with the reverse approach. Combined-approach patients had smaller tumors and underwent less complex hepatectomies. Larger LM, BRAF mutation, and TP53 mutation were independently associated with worse overall survival (OS) (p = 0.001, 0.001 and 0.048, respectively). Although 35% of reverse-approach patients did not undergo primary tumor resection, OS did not differ between groups (Figure 1), and 82% of reverse-approach patients did not require diversion during follow-up. RAS/TP53 co-mutation was independently associated with lack of primary resection with the reverse approach (odds ratio: 0.16, 95% CI: 0.038–0.64, p = 0.010).
Conclusion: The reverse approach results in survival similar to that with the combined and classic approaches and may obviate primary rectal tumor resections and diversions that do not improve oncologic outcome but affect quality of life. RAS/TP53 co-mutation is associated with lower rate of completion of the reverse approach.