Impact of a non-therapeutic laparotomy in patients with locally advanced pancreatic cancer treated with induction (m)FOLFIRINOX:Trans-Atlantic Pancreatic Surgery (TAPS) Consortium study

Background: Surgery in selected patients with locally advanced pancreatic cancer after induction chemotherapy may have drawbacks related to surgical risks and breaks or delays in oncological treatment, in particular when curative intent resection is not possible (that is non-therapeutic laparotomy). The aim of this study was to assess the incidence and oncological impact of a non-therapeutic laparotomy in patients with locally advanced pancreatic cancer treated with induction (m)FOLFIRINOX chemotherapy. Methods : This was a retrospective international multicentre study including patients diagnosed with pathology-proven locally advanced pancreatic cancer treated with at least one cycle of (m)FOLFIRINOX (2012–2019). Patients undergoing a non-therapeutic laparotomy (group A) were compared with those not undergoing surgery (group B) and those undergoing resection (group C). Results : Overall, 663 patients with locally advanced pancreatic cancer were included (67 patients (10.1%) in group A, 425 patients (64.1%) in group B, and 171 patients (25.8%) in group C). A non-therapeutic laparotomy occurred in 28.2% of all explorations (67 of 238), with occult metastases in 30 patients (30 of 67, 44.8%) and a 90-day mortality rate of 3.0% (2 of 67). Administration of palliative therapy (65.9% versus 73.1%; P = 0.307) and median overall survival (20.4 [95% c.i. 15.9 to 27.3] versus 20.2 [95% c.i. 19.1 to 22.7] months; P = 0.752) did not differ between group A and group B respectively. The median overall survival in group C was 36.1 (95% c.i. 30.5 to 41.2) months. The 5-year overall survival rates were 11.4%, 8.7%, and 24.7% in group A, group B, and group C, respectively. Compared with group B, non-therapeutic laparotomy (group A) was not associated with reduced overall survival (HR = 0.88 [95% c.i. 0.61 to 1.27]). Conclusion: More than a quarter of surgically explored patients with locally advanced pancreatic cancer after induction (m) FOLFIRINOX did not undergo a resection. Such non-therapeutic laparotomy does not appear to substantially impact oncological outcomes.</p

Predictive value of baseline serum carbohydrate antigen 19-9 level on treatment effect of neoadjuvant chemoradiotherapy in patients with resectable and borderline resectable pancreatic cancer in two randomized trials

BACKGROUND: Guidelines suggest that the serum carbohydrate antigen (CA19-9) level should be used when deciding on neoadjuvant treatment in patients with resectable and borderline resectable pancreatic ductal adenocarcinoma (hereafter referred to as pancreatic cancer). In patients with resectable pancreatic cancer, neoadjuvant therapy is advised when the CA19-9 level is 'markedly elevated'. This study investigated the impact of baseline CA19-9 concentration on the treatment effect of neoadjuvant chemoradiotherapy (CRT) in patients with resectable and borderline resectable pancreatic cancers.METHODS: In this post hoc analysis, data were obtained from two RCTs that compared neoadjuvant CRT with upfront surgery in patients with resectable and borderline resectable pancreatic cancers. The effect of neoadjuvant treatment on overall survival was compared between patients with a serum CA19-9 level above or below 500 units/ml using the interaction test.RESULTS: Of 296 patients, 179 were eligible for analysis, 90 in the neoadjuvant CRT group and 89 in the upfront surgery group. Neoadjuvant CRT was associated with superior overall survival (HR 0.67, 95 per cent c.i. 0.48 to 0.94; P = 0.019). Among 127 patients (70, 9 per cent) with a low CA19-9 level, median overall survival was 23.5 months with neoadjuvant CRT and 16.3 months with upfront surgery (HR 0.63, 0.42 to 0.93). For 52 patients (29 per cent) with a high CA19-9 level, median overall survival was 15.5 months with neoadjuvant CRT and 12.9 months with upfront surgery (HR 0.82, 0.45 to 1.49). The interaction test for CA19-9 level exceeding 500 units/ml on the treatment effect of neoadjuvant CRT was not significant (P = 0.501).CONCLUSION: Baseline serum CA19-9 level defined as either high or low has prognostic value, but was not associated with the treatment effect of neoadjuvant CRT in patients with resectable and borderline resectable pancreatic cancers, in contrast with current guideline advice.</p

Serum CEA as a Prognostic Marker for Overall Survival in Patients with Localized Pancreatic Adenocarcinoma and Non-Elevated CA19-9 Levels Treated with FOLFIRINOX as Initial Treatment:A TAPS Consortium Study

Introduction: About 25% of patients with localized pancreatic adenocarcinoma have non-elevated serum carbohydrate antigen (CA) 19-9 levels at baseline, hampering evaluation of response to preoperative treatment. Serum carcinoembryonic antigen (CEA) is a potential alternative. Methods: This retrospective cohort study from five referral centers included consecutive patients with localized pancreatic adenocarcinoma (2012–2019), treated with one or more cycles of (m)FOLFIRINOX, and non-elevated CA19-9 levels (i.e., &lt; 37 U/mL) at baseline. Cox regression analyses were performed to assess prognostic factors for overall survival (OS), including CEA level at baseline, restaging, and dynamics. Results: Overall, 277 patients were included in this study. CEA at baseline was elevated (≥5 ng/mL) in 53 patients (33%) and normalized following preoperative therapy in 14 patients (26%). In patients with elevated CEA at baseline, median OS in patients with CEA normalization following preoperative therapy was 33 months versus 19 months in patients without CEA normalization (p = 0.088). At time of baseline, only elevated CEA was independently associated with (worse) OS (hazard ratio [HR] 1.44, 95% confidence interval [CI] 1.04–1.98). At time of restaging, elevated CEA at baseline was still the only independent predictor for (worse) OS (HR 1.44, 95% CI 1.04–1.98), whereas elevated CEA at restaging (HR 1.16, 95% CI 0.77–1.77) was not. Conclusions: Serum CEA was elevated in one-third of patients with localized pancreatic adenocarcinoma having non-elevated CA19-9 at baseline. At both time of baseline and time of restaging, elevated serum CEA measured at baseline was the only predictor for (worse) OS. Therefore, serum CEA may be a useful tool for decision making at both initial staging and time of restaging in patients with non-elevated CA19-9.</p

FOLFIRINOX as Initial Treatment for Localized Pancreatic Adenocarcinoma: A Retrospective Analysis by the Trans-Atlantic Pancreatic Surgery Consortium

Background: Large pragmatic studies of patients who received 5-fluorouracil with leucovorin, irinotecan, and oxaliplatin ([m]FOLFIRINOX) as initial treatment for localized pancreatic ductal adenocarcinoma (PDAC) are lacking. This study aimed to provide realistic estimates of oncologic outcomes in these patients. Methods: This international retrospective cohort study included all consecutive patients presenting with localized PDAC who received at least 1 cycle of (m)FOLFIRINOX as initial treatment in 5 referral centers from the United States and the Netherlands (2012-2019). Primary outcome was median overall survival (OS), calculated from the date of tissue diagnosis, assessed using Kaplan-Meier estimates. Log-rank test was used to compare OS between groups. A Cox proportional hazards regression model was used to assess prognostic baseline factors for OS. All statistical tests were 2-sided. Results: Overall, 1835 patients were included, of whom 958 (52.2%) had locally advanced (LA), 531 (28.9%) had borderline resectable (BR), and 346 (18.9%) had potentially resectable (PR) PDAC. The median number of (m)FOLFIRINOX cycles was 6 (interquartile range = 4-8). Subsequent treatment included second chemotherapy (12.9%), radiotherapy (49.0%), and resection (37.9%). The resection rate was 17.6% for LA, 53.1% for BR, and 70.5% for PR PDAC (P 1 mm) was 55.2% for LA, 62.6% for BR, and 79.2% for PR PDAC (P 500 U/mL, and body mass index ≤18.5 kg/m2. Conclusions: This large international cohort study provides realistic estimates of resection rates and survival in patients with LA, BR, and PR PDAC who started (m)FOLFIRINOX treatment in PDAC referral centers

Neoadjuvant Radiotherapy After (m)FOLFIRINOX for Borderline Resectable Pancreatic Adenocarcinoma: A TAPS Consortium Study

BACKGROUND: The value of neoadjuvant radiotherapy (RT) after 5-fluorouracil with leucovorin, oxaliplatin, and irinotecan, with or without dose modifications [(m)FOLFIRINOX], for patients with borderline resectable (BR) pancreatic ductal adenocarcinoma (PDAC) is uncertain. METHODS: We conducted an international retrospective cohort study including consecutive patients with BR PDAC who received (m)FOLFIRINOX as initial treatment (2012-2019) from the Trans-Atlantic Pancreatic Surgery Consortium. Because the decision to administer RT is made after chemotherapy, patients with metastases or deterioration after (m)FOLFIRINOX or a performance score ≥2 were excluded. Patients who received RT after (m)FOLFIRINOX were matched 1:1 by nearest neighbor propensity scores with patients who did not receive RT. Propensity scores were calculated using sex, age (≤70 vs >70 years), WHO performance score (0 vs 1), tumor size (0-20 vs 21-40 vs >40 mm), tumor location (head/uncinate vs body/tail), number of cycles (1-4 vs 5-8 vs >8), and baseline CA 19-9 level (≤500 vs >500 U/mL). Primary outcome was overall survival (OS) from diagnosis. RESULTS: Of 531 patients who received neoadjuvant (m)FOLFIRINOX for BR PDAC, 424 met inclusion criteria and 300 (70.8%) were propensity score-matched. After matching, median OS was 26.2 months (95% CI, 24.0-38.4) with RT versus 32.8 months (95% CI, 25.3-42.0) without RT (P=.71). RT was associated with a lower resection rate (55.3% vs 72.7%; P=.002). In patients who underwent a resection, RT was associated with a comparable margin-negative resection rate (>1 mm) (70.6% vs 64.8%; P=.51), more node-negative disease (57.3% vs 37.6%; P=.01), and more major pathologic response with <5% tumor viability (24.7% vs 8.3%; P=.006). The OS associated with conventional and stereotactic body RT approaches was similar (median OS, 25.7 vs 26.0 months; P=.92). CONCLUSIONS: In patients with BR PDAC, neoadjuvant RT following (m)FOLFIRINOX was associated with more node-negative disease and better pathologic response in patients who underwent resection, yet no difference in OS was found. Routine use of RT cannot be recommended based on these data

Minimum and Optimal CA19-9 Response After Two Months Induction Chemotherapy in Patients with Locally Advanced Pancreatic Cancer:A Nationwide Multicenter Study

OBJECTIVE: This nationwide multicenter study aimed to define clinically relevant thresholds of relative serum CA19-9 response after 2 months induction chemotherapy in patients with locally advanced pancreatic cancer (LAPC). SUMMARY BACKGROUND DATA: CA19-9 is seen as leading biomarker for response evaluation in patients with LAPC, but early clinically useful cut-offs are lacking. METHODS: All consecutive patients with LAPC after 4 cycles (m)FOLFIRINOX or 2 cycles gemcitabine-nab-paclitaxel induction chemotherapy (±radiotherapy) with CA19-9 =5 U/mL at baseline were analyzed (2015-2019). The association of CA19-9 response with median OS (mOS) was evaluated for different CA19-9 cut-off points. Minimum and optimal CA19-9 response were established via log-rank test. Predictors for OS were analyzed, using cox regression analysis. RESULTS: Overall, 212 patients were included of whom 42 (19.8%) underwent resection. Minimum CA19-9 response demonstrating a clinically significant mOS difference (12.7 vs. 19.6 mo) was seen at =40% CA19-9 decrease. The optimal cut-off for CA19-9 response was =60% decrease (21.7 vs. 14.0 mo, P=0.021). Only for patients with elevated CA19-9 levels at baseline (n=184), CA19-9 decrease =60% (HR=0.59, 95%CI 0.36-0.98, P=0.042) was independently associated with prolonged OS, as were SBRT (HR=0.42, 95%CI 0.25-0.70; P=0.001), and resection (HR=0.25, 95%CI 0.14-0.46, P&lt;0.001), and duration of chemotherapy (HR=0.75, 95%CI 0.69-0.82, P&lt;0.001). CONCLUSION: CA19-9 decrease of =60% following induction chemotherapy as optimal response cut-off in patients with LAPC is an independent predictor for OS when CA19-9 is increased at baseline. Furthermore, =40% is the minimum cut-off demonstrating survival benefit. These cut-offs may be used when discussing treatment strategies during early response evaluation