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. 2024 Jun 18;7(6):e2417625. doi: 10.1001/jamanetworkopen.2024.17625

Pathological Complete Response in Patients With Resected Pancreatic Adenocarcinoma After Preoperative Chemotherapy

Thomas F Stoop 1,2,3,✉, Atsushi Oba 1,4,5, Y H Andrew Wu 1,6,7, Laurel E Beaty 8, Kathryn L Colborn 9,10, Boris V Janssen 2,3,11, Mohammed H Al-Musawi 12, Salvador Rodriguez Franco 1, Toshitaka Sugawara 1,5, Oskar Franklin 1,13, Ajay Jain 14, Akio Saiura 15, Alain Sauvanet 16, Alessandro Coppola 17, Ammar A Javed 2,3,6,7,18, Bas Groot Koerkamp 19, Braden N Miller 14, Claudia E Mack 20, Daisuke Hashimoto 21, Damiano Caputo 22,23, Dyre Kleive 24, Elisabetta Sereni 6,7,25, Giulio Belfiori 26, Hirofumi Ichida 15, Jacob L van Dam 19, Jeanne Dembinski 16, Keiichi Akahoshi 5, Keith J Roberts 27, Kimitaka Tanaka 28, Knut J Labori 24, Massimo Falconi 26, Michael G House 29, Motokazu Sugimoto 30, Minoru Tanabe 5, Naoto Gotohda 30, Paul S Krohn 31, Richard A Burkhart 6,7, Rohan G Thakkar 32, Rupaly Pande 27, Safi Dokmak 16, Satoshi Hirano 28, Stefan K Burgdorf 31, Stefano Crippa 26, Stijn van Roessel 2,3, Sohei Satoi 1,21, Steven A White 32, Thilo Hackert 33, Trang K Nguyen 29, Tomohisa Yamamoto 21, Toru Nakamura 28, Vismaya Bachu 6,7, William R Burns 6,7, Yosuke Inoue 4, Yu Takahashi 4, Yuta Ushida 4, Zohra V Aslami 6,7, Caroline S Verbeke 34, Arantza Fariña 3,11, Jin He 6,7, Johanna W Wilmink 3,35, Wells Messersmith 36, Joanne Verheij 3,11, Jeffrey Kaplan 37, Richard D Schulick 1, Marc G Besselink 2,3, Marco Del Chiaro 1
PMCID: PMC11185983  PMID: 38888920

Key Points

Question

What are the incidence, outcome, and associated factors of pathological complete response (pCR) in patients with resected pancreatic adenocarcinoma after chemo(radio)therapy?

Findings

This cohort study of 1758 patients found a pCR rate of 4.8%, which was associated with longer overall survival compared with no pCR. Factors associated with pCR included preoperative (modified) FOLFIRINOX, preoperative radiotherapy (particularly stereotactic body radiation therapy), radiologic response, and normal(ized) serum carbohydrate antigen 19-9.

Meaning

Although pCR does not reflect cure, these findings suggest that it is associated with improved OS, and the identified factors associated with pCR may have implications for treatment strategies.

This cohort study analyzes the incidence, outcome, and factors associated with pathological complete response in patients with pancreatic adenocarcinoma who underwent preoperative chemo(radio)therapy followed by surgical resection.

Abstract

Importance

Preoperative chemo(radio)therapy is increasingly used in patients with localized pancreatic adenocarcinoma, leading to pathological complete response (pCR) in a small subset of patients. However, multicenter studies with in-depth data about pCR are lacking.

Objective

To investigate the incidence, outcome, and risk factors of pCR after preoperative chemo(radio)therapy.

Design, Setting, and Participants

This observational, international, multicenter cohort study assessed all consecutive patients with pathology-proven localized pancreatic adenocarcinoma who underwent resection after 2 or more cycles of chemotherapy (with or without radiotherapy) in 19 centers from 8 countries (January 1, 2010, to December 31, 2018). Data collection was performed from February 1, 2020, to April 30, 2022, and analyses from January 1, 2022, to December 31, 2023. Median follow-up was 19 months.

Exposures

Preoperative chemotherapy (with or without radiotherapy) followed by resection.

Main Outcomes and Measures

The incidence of pCR (defined as absence of vital tumor cells in the sampled pancreas specimen after resection), its association with OS from surgery, and factors associated with pCR. Factors associated with overall survival (OS) and pCR were investigated with Cox proportional hazards and logistic regression models, respectively.

Results

Overall, 1758 patients (mean [SD] age, 64 [9] years; 879 [50.0%] male) were studied. The rate of pCR was 4.8% (n = 85), and pCR was associated with OS (hazard ratio, 0.46; 95% CI, 0.26-0.83). The 1-, 3-, and 5-year OS rates were 95%, 82%, and 63% in patients with pCR vs 80%, 46%, and 30% in patients without pCR, respectively (P < .001). Factors associated with pCR included preoperative multiagent chemotherapy other than (m)FOLFIRINOX ([modified] leucovorin calcium [folinic acid], fluorouracil, irinotecan hydrochloride, and oxaliplatin) (odds ratio [OR], 0.48; 95% CI, 0.26-0.87), preoperative conventional radiotherapy (OR, 2.03; 95% CI, 1.00-4.10), preoperative stereotactic body radiotherapy (OR, 8.91; 95% CI, 4.17-19.05), radiologic response (OR, 13.00; 95% CI, 7.02-24.08), and normal(ized) serum carbohydrate antigen 19-9 after preoperative therapy (OR, 3.76; 95% CI, 1.79-7.89).

Conclusions and Relevance

This international, retrospective cohort study found that pCR occurred in 4.8% of patients with resected localized pancreatic adenocarcinoma after preoperative chemo(radio)therapy. Although pCR does not reflect cure, it is associated with improved OS, with a doubled 5-year OS of 63% compared with 30% in patients without pCR. Factors associated with pCR related to preoperative chemo(radio)therapy regimens and anatomical and biological disease response features may have implications for treatment strategies that require validation in prospective studies because they may not universally apply to all patients with pancreatic adenocarcinoma.

Introduction

The treatment of localized pancreatic adenocarcinoma has evolved during the past decade with the increasing use of preoperative chemo(radio)therapy, particularly multiagent chemotherapeutic regimens.1 Preoperative therapy provides the chance for improved disease control while selecting patients with more favorable tumor biology for surgical resection,2 leading to resection rates of 77%, 61%, and 22% among patients with primary resectable, borderline resectable, and locally advanced pancreatic cancer, respectively.3

Nevertheless, the interpretation of anatomical, biological, and conditional parameters for personalized restaging remains challenging,4,5,6 illustrated by high early recurrence rates.7,8 Histopathological residual tumor burden after resection following preoperative therapy is 1 of the biological parameters for disease response.9,10,11 The presence and extent of vital tumor burden are considered a surrogate marker for the tumor’s response on preoperative therapy, which could be used for prognostication and may guide the decision-making for adjuvant therapy.12 Pathological complete response (pCR) is the ultimate tumor response, with an estimated incidence of 4%.13

Radiation therapy and longer duration of preoperative chemotherapy have been suggested to be associated with pCR.14 Pathological complete response is associated with improved overall survival (OS), with a median up to 100 months,14,15,16,17 although up to half of patients with pCR develop disease recurrence.16,17,18 However, evidence regarding pCR is based on large national databases with limited granularity or small single-center series.13,14,15,16,19,20,21,22,23,24 Better insight into the outcomes and factors associated with pCR may contribute to the improvement of preoperative therapy in patients with pancreatic adenocarcinoma, improving selection for surgery and prognostication. Therefore, the current international, observational, multicenter cohort study aimed to perform an in-depth analysis on the incidence, outcome, and factors associated with pCR within a large cohort of consecutive patients with pancreatic adenocarcinoma who underwent preoperative chemo(radio)therapy followed by surgical resection.

Methods

This retrospective, observational, multicenter cohort study was performed in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.25 The study procedures were reviewed and approved by the Colorado Multiple Institutional Review Board at the University of Colorado. The need for informed consent was waived by the institutional review board because of the retrospective nature of this study.

Study Design and Patients

All consecutive adult patients (aged ≥18 years) were retrospectively included from institutional databases in 19 centers from 8 countries who underwent any type of pancreatic resection after preoperative chemo(radio)therapy (January 1, 2010, to December 31, 2018) for localized pancreatic adenocarcinoma. Exclusion criteria included fewer than 2 cycles of preoperative chemotherapy, unknown type of preoperative chemotherapy, and pCR cases without preoperative cytologic or histologic test results classified as “suspicious for malignancy” or “positive/malignant.”26 The arbitrary cutoff of fewer than 2 cycles of preoperative chemotherapy was selected to approach the daily clinical practice by reducing the selection. Because of the differently used tumor regression grading classification,27 the interobserver variability,28,29 and differences in sampling strategies12,30 among centers and pathologists around the world, the current study focused on comparing patients with pCR vs without pCR. Data on patient race and ethnicity were not collected because it was not considered during the design of this study.

Definitions

The American Society of Anesthesiologists Physical Status was used to indicate patients’ conditional status. Pancreatic adenocarcinoma was staged using the TNM Classification of Malignant Tumours (7th edition) and the National Comprehensive Cancer Network guideline, version 1.2019.31,32 If the tumor involved multiple anatomical locations in the pancreas (ie, head, body, and/or tail), the most proximal location was registered.

When a patient underwent a chemotherapy switch preoperatively, the dominant chemotherapeutic regimen was used, whereby other chemotherapy lines were registered as second-line chemotherapy. The following strategy was used to determine the dominant regimen. First, if both regimens were single-agent or multiagent chemotherapy but the number of administered cycles from both regimens was not available, the last regimen before surgery was considered as the dominant regimen. If the number of cycles from all regimens was available, the chemotherapeutic regimen with the most administered cycles was used as the dominant regimen. Second, if multiple lines were given, including a multiagent and single-agent chemotherapy, the multiagent chemotherapy was defined as the dominant regimen, regardless of the order or number of cycles. Third, systemic chemotherapy was considered superior to intraperitoneal-administered chemotherapy. Additional experimental drugs were not taken into account. The interval between the start of preoperative chemotherapy and surgery was used as a surrogate marker for the preoperative treatment duration. The duration was stratified into less than 4, 4 to less than 6, 6 or more to less than 12, and 12 or more months.

Radiological response evaluation was defined in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST) criteria.33 A carbohydrate antigen 19-9 (CA 19-9) level of 37 U/mL or greater and a carcinoembryonic antigen (CEA) level greater than 5 ng/mL (to convert to micrograms per liter, multiply by 1) were considered elevated.

Type and extent of pancreatic surgery were defined using the International Study Group for Pancreatic Surgery definition.34 Major morbidity was defined as a Clavien-Dindo grade of IIIa or higher within 90 days after surgery.35 Radicality (R0 vs R1) was classified following the Royal College of Pathologist definition.36 Pathological complete response was defined as the absence of any vital tumor tissue in the sampled pancreatic resection specimen.

Recurrence-free survival (RFS) and OS were measured from the time of surgery. Additionally, the OS measured from the start of preoperative chemotherapy was provided. From the date of surgery, follow-up was measured until death or the most recent date alive. Data collection ranged from February 1, 2020, to April 30, 2022, and analyses were performed between January 1, 2022, and December 31, 2023.

Statistical Analysis

Data analyses were performed using R software, version 4.2.2 (R Foundation for Statistical Computing).37 Statistical significance was determined using a 2-sided P < .05. Patients with and without pCR were compared using descriptive statistics. Bivariable statistics were estimated using χ2 or Fisher exact (when observed cell counts were <5) tests for categorical data. Normally distributed continuous variables were compared using the Welch independent 2-sample t test, and the Wilcoxon rank sum test was used for nonnormally distributed data.

The amount of missing data per variable ranged from 0% to more than 50%. Data appeared to be missing not at random for larger counts of missing data. Therefore, a missing data category was introduced for each categorical variable that was missing 2% or more; otherwise, patients with missing data for variables missing less than 2% were simply quantified and displayed as counts in bivariable comparisons. If a categorical variable had less than 2% missing data, the missing patients were not included in the overall proportions reported, and they were not included in the test of association because of a lack of power. If a categorical variable had missing data of 2% or more, these patients were classified as missing and included in the overall proportions and the test of association. For all continuous variables, the missing data were not included in the test of association.

Serum CA 19-9 was treated as a categorical variable because there were substantial missing data for this variable (so we needed to include a missing data category) and because the association between this variable and the outcomes was nonlinear. Furthermore, the groupings chosen for this variable were considered clinically meaningful. For the relative change in serum CA 19-9 between diagnosis and restaging, the area under the curve method was used to select the optimal threshold among patients with elevated serum CA 19-9 at diagnosis who showed any degree of reduction.

The median RFS and OS times with 95% CIs were calculated using the Kaplan-Meier method, and subgroups were compared using the log-rank test using the survival package in R.38,39 Univariable (unadjusted) and multivariable (adjusted) Cox proportional hazards regression models were used to assess the association between clinical parameters and OS measured from surgery using the survival package in R.38,39 The OS from surgery was used so that the findings can be used for prognostication immediately after surgery, because pCR is only known at that time. The results are presented in hazard ratios (HRs) with 95% CIs.

Univariable and multivariable logistic regression models were used to assess factors associated with pCR using the stats package in R.37 The results are presented as odds ratios (OR) with 95% CIs. For both the Cox proportional hazards and logistic regression models, the following strategy was used. The univariable models included all variables that were considered clinically relevant based on the literature and clinical experience. Independent variables with P < .25 were included in the multivariable models.

Due to collinearity among the 3 serum CA 19-9 variables, only the serum CA 19-9 parameter with the strongest bivariable statistical association was tested in the multivariable analysis, based on P value. Again, missing data were included as a category if they were missing for at least 2% of patients. Otherwise, missing data were excluded for variables missing less than 2% of the time. In the bivariable analyses, if the only significant comparison within a categorical variable was for the missing group, the variable was not included in the multivariable analysis.

Results

Overall, 1758 patients (mean [SD] age, 64 [9] years; 879 [50.0%] male and 879 [50.0%] female) underwent resection of pancreatic adenocarcinoma after chemo(radio)therapy and were included from 4 centers in the US (798 patients [45.4%]), 6 centers in Japan (366 patients [20.8%]), and 9 centers in Europe (594 patients [33.8%]). The number of patients per center ranged from 5 to 397. Of the 1758 included patients, 85 (4.8%) were diagnosed with pCR, with a median incidence of 3.8% (IQR, 0.3%-7.8%) per center. See eAppendix 1 in Supplement 1 for the incidences of pCR per center.

Clinicopathological Details

At time of diagnosis, pancreatic adenocarcinoma was staged as primary resectable (n = 429 [24.5%]), borderline resectable (n = 856 [48.9%]), or locally advanced (n = 465 [26.6%]). The primary tumor was mostly located in the pancreatic head (n = 1276 [72.6%]). The median (IQR) serum CA 19-9 level before preoperative therapy was 183 (46-626) U/mL, without a difference between patients with or without pCR. See Table 1 for baseline characteristics at time of diagnosis.

Table 1. Baseline Characteristics at Diagnosisa.

Characteristic Overall cohort (N = 1758) pCR (n = 85) No pCR (n = 1673) P valueb
Age, mean (SD), y 64 (9) 62 (9) 64 (9) .01c
Sex
Female 879 (50.0) 41 (48.2) 838 (50.1) .74d
Male 879 (50.0) 44 (51.8) 835 (49.9)
ASA-PS
I-II 1295 (74.0) 45 (52.9) 1250 (75.0) <.001d
III-IV 456 (26.0) 40 (47.1) 416 (25.0)
Missing 7 0 7
Resectability
Primary resectable 429 (24.5) 6 (7.1) 423 (25.4) <.001d
Borderline resectable 856 (48.9) 43 (50.6) 813 (48.8)
Locally advanced 465 (26.6) 36 (42.4) 429 (25.8)
Missing 8 0 8
Tumor location
Pancreatic head 1276 (72.6) 71 (83.5) 1205 (72.1) .02d
Pancreatic body or tail 481 (27.4) 14 (16.5) 467 (27.9)
Missing 1 0 1
Tumor size, mm
≤20 385 (22.2) 9 (11.3) 376 (22.7) .005d
21-40 1095 (63.1) 51 (63.8) 1044 (63.1)
>40 255 (14.7) 20 (25.0) 235 (14.2)
Missing 23 5 18
cT stage .10d
T1/T2 425 (24.2) 27 (31.8) 398 (23.8)
T3/T4 1332 (75.8) 58 (68.2) 1274 (76.2)
Missing 1 0 1
CA 19-9, U/mL
Median (IQR) 183 (46-626) 105 (31-475) 185 (48-633) .11e
<37 317 (18.0) 16 (18.8) 301 (18.0) <.001d
≥37 to <150 342 (19.5) 17 (20.0) 325 (19.4)
≥150 to <500 360 (20.5) 8 (9.4) 352 (21.0)
≥500 to <1000 156 (8.9) 6 (7.1) 150 (9.0)
≥1000 259 (14.7) 8 (9.4) 251 (15.0)
Missing 324 (18.4) 30 (35.3) 294 (17.6)
CEA
Median (IQR), ng/mL 3.1 (2.1-5.3) 2.6 (2.1-4.4) 3.2 (2.1-5.4) .41e
Normal 633 (36.0) 21 (24.7) 612 (36.6) <.001f
>5 to ≤20 204 (11.6) 2 (2.4) 202 (12.1)
>20 34 (1.9) 2 (2.4) 32 (1.9)
Missing 887 (50.5) 60 (70.6) 827 (49.4)
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Abbreviations: ASA-PS, American Society of Anesthesiologists Performance Status; CA 19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; pCR, pathological complete response.

SI conversion factor: To convert CEA to micrograms per liter, multiply by 1.

a

Data are presented as number (percentage) of patients unless otherwise indicated. Categorical data with missing data for 2% or more of patients were included in a separate category and were therefore included in the overall proportions and in the test of association. Otherwise, for missing data less than 2%, the data are shown but were not included in the hypothesis tests. See eAppendix 4 in Supplement 1 for the presentation of these data using row percentages.

b

Comparison between patients with or without pCR.

c

Welch independent 2-sample t test.

d

χ2 test.

e

Wilcoxon rank sum test.

f

Fisher exact test.

Preoperative Therapy and Disease Response

Most patients were treated with preoperative (modified) leucovorin calcium (folinic acid), fluorouracil, irinotecan hydrochloride, and oxaliplatin ([m]FOLFIRINOX) (n = 797 [45.3%]) or gemcitabine and nab-paclitaxel (n = 501 [28.5%]). Patients with pCR were more frequently treated with preoperative (m)FOLFIRINOX compared with patients without pCR (n = 50 of 85 [58.8%] vs 747 of 1673 [44.7%]; P < .001). Concomitant radiotherapy was administered in 872 patients (50.0%). The rate of radiation therapy was higher among patients with pCR compared with patients without pCR (n = 68 of 85 [80.0%] vs 804 of 1658 [48.5%]; P < .001). See Table 2 for details regarding preoperative therapy and response evaluation.

Table 2. Preoperative Therapy and Disease Responsea.

Variable Patients, No. (%) P valueb
Overall cohort (N = 1758) pCR (n = 85) No pCR (n = 1673)
Preoperative therapy
Chemotherapy
(m)FOLFIRINOX 797 (45.3) 50 (58.8) 747 (44.7) <.001c
Gemcitabine and nab-paclitaxel 501 (28.5) 11 (12.9) 490 (29.3)
Gemcitabine–S-1 100 (5.7) 1 (1.2) 99 (5.9)
Gemcitabine-oxaliplatin 101 (5.7) 2 (2.4) 99 (5.9)
Other multiagent regimens 90 (5.1) 9 (10.6) 81 (4.8)
Gemcitabine 97 (5.5) 7 (8.2) 90 (5.4)
S-1 53 (3.0) 2 (2.4) 51 (3.0)
Other single-agent regimens 19 (1.1) 3 (3.5) 16 (1.0)
Second-line chemotherapy 216 (12.3) 13 (15.3) 203 (12.1) .55c
Missing 74 (4.2) 2 (2.4) 72 (4.3)
Chemotherapy dose reduction 250 (14.2) 6 (7.1) 244 (14.6) <.001d
Missing 660 (37.5) 57 (67.1) 603 (36.0)
Radiotherapy
No 871 (50.0) 17 (20.0) 854 (51.5) <.001d
Yes, conventional radiotherapy 462 (26.5) 37 (43.5) 425 (25.6)
Yes, SBRT 410 (23.5) 31 (36.5) 379 (22.9)
Missing 15 0 15
Preoperative therapy duration, mo
<4 475 (27.0) 16 (18.8) 459 (27.4) <.001c
≥4 to <6 469 (26.7) 16 (18.8) 453 (27.1)
≥6 to <12 637 (36.2) 34 (40.0) 603 (36.0)
≥12 118 (6.7) 16 (18.8) 102 (6.1)
Missing 59 (3.4) 3 (3.5) 56 (3.3)
Response evaluation
RECIST
Complete response 14 (0.8) 4 (4.7) 10 (0.6) <.001c
Partial response 506 (29.1) 61 (71.8) 445 (26.9)
Stable disease 1194 (68.7) 19 (22.4) 1175 (71.0)
Progressive disease 25 (1.4) 1 (1.2) 24 (1.5)
Missing 19 0 19
CA 19-9
Median (IQR), U/mL 36 (15-92) 19 (13-35) 37 (15-95) .003e
Normal 773 (44.0) 43 (50.6) 730 (43.6) <.001c
≥37 to <150 U/mL 493 (28.0) 7 (8.2) 486 (29.0)
≥150 to <500 U/mL 170 (9.7) 3 (3.5) 167 (10.0)
≥500 to <1000 U/mL 37 (2.1) 1 (1.2) 36 (2.2)
≥1000 U/mL 40 (2.3) 0 40 (2.4)
Missing 245 (13.9) 31 (36.5) 214 (12.8)
CA 19-9 patterns
Normal to normal 281 (16.0) 12 (14.1) 269 (16.1) <.001c
Normal to elevated 17 (1.0) 1 (1.2) 16 (1.0)
Elevated to normal 415 (23.6) 23 (27.1) 392 (23.4)
Elevated to elevated 655 (37.3) 10 (11.8) 645 (38.6)
Missing 390 (22.2) 39 (45.9) 351 (21.0)
Relative CA 19-9 change
No change or increased 93 (5.3) 2 (2.4) 91 (5.4) <.001c
Decreased <87% 538 (30.6) 9 (10.6) 529 (31.6)
Decreased ≥87% 439 (25.0) 22 (25.9) 417 (24.9)
<37 U/mL at time of diagnosis 317 (18.0) 16 (18.8) 301 (18.0)
Missing 371 (21.1) 36 (42.4) 335 (20.0)
CEA
Median (IQR), ng/mL 2.9 (2.0-4.6) 2.9 (1.8-4.2) 2.9 (2.0-4.6) .85e
Normal 744 (42.3) 21 (24.7) 723 (43.2) <.001c
>5 to ≤20 ng/mL 189 (10.8) 3 (3.5) 186 (11.1)
>20 ng/mL 20 (1.1) 0 20 (1.2)
Missing 805 (45.8) 61 (71.8) 744 (44.5)
CEA patterns
Normal to normal 520 (29.6) 13 (15.3) 507 (30.3) <.001c
Normal to elevated 53 (3.0) 1 (1.2) 52 (3.1)
Elevated to normal 100 (5.7) 2 (2.4) 98 (5.9)
Elevated to elevated 110 (6.3) 0 110 (6.6)
Missing 975 (55.5) 69 (81.2) 906 (54.2)
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Abbreviations: CA 19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; (m)FOLFIRINOX, (modified) leucovorin calcium (folinic acid), fluorouracil, irinotecan hydrochloride, and oxaliplatin; pCR, pathological complete response; RECIST, Response Evaluation Criteria in Solid Tumors; SBRT, stereotactic body radiotherapy.

SI conversion factor: To convert CEA to micrograms per liter, multiply by 1.

a

Data are presented as number (percentage) of patients unless otherwise indicated. Categorical data with missing data for 2% or more of patients were included in a separate category and were therefore included in the overall proportions and in the test of association. Otherwise, for missing less than 2%, the data are shown but were not included in the hypothesis tests. See eAppendix 4 in Supplement 1 for the presentation of these data using row percentages.

b

Comparison between patients with or without pCR.

c

Fisher exact test.

d

χ2 test.

e

Wilcoxon rank sum test.

Surgery Outcome

Pancreatoduodenectomy was the most commonly performed surgical procedure (n = 1262 [71.8%]). An extended resection was performed in 696 patients (39.6%). The rates of vascular resection among patients with a primary resectable, borderline resectable, and locally advanced tumor were 16.1% (n = 69 of 429), 39.6% (n = 339 of 855 [missing n = 1]), and 44.3% (n = 206 of 465), respectively. The 90-day mortality was 3.2% (n = 55). See eAppendix 2 in Supplement 1 for further details on surgical procedures and outcome and eAppendix 3 in Supplement 1 for histopathological outcomes. Patients with pCR received adjuvant chemotherapy (n = 30 of 85 [35.3%]) less frequently than patients without pCR (n = 1120 of 1673 [66.9%]) (P < .001).

Oncologic Outcome

Follow-up data were available from 1757 of the 1758 patients, of whom 817 patients (46.5%) died. The median (IQR) follow-up time was 19 (11-33) months. The median OS from the total cohort was 33 months (95% CI, 31-37 months) (Figure, A). The median OS outcomes of patients with a primary resectable, borderline resectable, or locally advanced tumor were 43 (95% CI, 36-49), 31 (95% CI, 27-35), and 31 (95% CI, 26-36) months (P = .19), respectively. The median OS was shorter in patients who underwent a vascular resection compared with no vascular resection: 28 (95% CI, 26-31) vs 38 (95% CI, 33-43) months (P < .001), respectively.

Figure. Kaplan-Meier Survival Curves.

Figure.

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pCR indicates pathological complete response.

When comparing patients with and without pCR, the median OS was not reached in the pCR group, whereas the median OS was 31 (95% CI, 30-35) months in patients without pCR (P < .001). In patients with pCR, the 1-, 3-, and 5-year OS rates were 95% (95% CI, 90%-100%), 82% (95% CI, 73%-93%), and 63% (95% CI, 47%-86%), respectively. In patients without pCR, the 1-, 3-, and 5-year OS rates were 80% (95% CI, 78%-82%), 46% (95% CI, 44%-49%), and 30% (95% CI, 27%-34%), respectively (Figure, B). See eAppendix 5 in Supplement 1 for OS outcomes measured from the start of preoperative chemotherapy.

For the analysis on RFS, 50 patients had missing data on recurrence status (n = 18) and/or date of disease recurrence (n = 33). Therefore, these patients were excluded from this analysis. Among the 1708 patients with data about disease recurrence, 1036 (60.7%) developed disease recurrence. In the overall study cohort, the median RFS was 16 months (95% CI, 14-17 months) (Figure, C). The median RFS was not reached in the patients with pCR, whereas the median RFS was 15 months (95% CI, 14-16 months) in patients without pCR (P < .001) (Figure, D). See eAppendix 6 in Supplement 1 for the comparison of recurrence location between patients with or without pCR. After adjustment for potential confounders, pCR was associated with prolonged OS (HR, 0.46; 95% CI, 0.26-0.83). See Table 3 for the Cox proportional hazards regression analysis.

Table 3. Cox Proportional Hazards Regression Model for Estimating Associations Between Risk Factors and Mortality.

Variable No. of patients (N = 1677) Univariable analysis Multivariable analysis
HR (95% CI) P value HR (95% CI) P value
Gender
Female 842 1 [Reference] NA 1 [Reference] NA
Male 835 1.11 (0.96-1.28) .15 1.09 (0.94-1.25) .27
ASA-PS
I-II 1242 1 [Reference] NA NA NA
III-IV 435 1.06 (0.90-1.25) .49 NA NA
Tumor location
Body or tail 458 1 [Reference] NA NA NA
Head 1219 0.94 (0.81-1.10) .47 NA NA
Tumor size at diagnosis, mm
≤20 374 1 [Reference] NA 1 [Reference] NA
21-40 1059 1.31 (1.09-1.58) .004 1.08 (0.88-1.33) .46
>40 244 1.41 (1.11-1.80) .006 0.79 (0.59-1.06) .12
Resectability at diagnosis
Primary resectable 417 1 [Reference] NA 1 [Reference] NA
Borderline resectable 819 1.14 (0.96-1.37) .14 1.05 (0.86-1.28) .62
Locally advanced 441 1.22 (1.00-1.49) .05 1.16 (0.92-1.45) .20
CA 19-9 at diagnosis, U/mL
<37 305 1 [Reference] NA NA NA
≥37 to <150 330 0.81 (0.64-1.02) .07 NA NA
≥150 to <500 340 1.09 (0.88-1.36) .43 NA NA
≥500 to <1000 146 0.95 (0.71-1.28) .76 NA NA
≥1000 249 1.21 (0.95-1.52) .12 NA NA
Missing 307 0.77 (0.60-0.98) .03 NA NA
Preoperative chemotherapy
(m)FOLFIRINOX 764 1 [Reference] NA NA NA
Other multiagent 754 1.06 (0.92-1.24) .42 NA NA
Single agent 159 1.03 (0.81-1.31) .80 NA NA
Preoperative radiotherapy
None 835 1 [Reference] NA 1 [Reference] NA
Conventional radiotherapy 446 0.79 (0.66-0.94) .008 0.97 (0.79-1.19) .75
SBRT 396 1.09 (0.91-1.29) .34 1.27 (1.04-1.56) .02
Preoperative therapy duration, mo
<4 452 1 [Reference] NA NA NA
≥4 to <6 452 0.88 (0.73-1.07) .20 NA NA
≥6 to <12 609 1.03 (0.86-1.22) .76 NA NA
≥12 111 0.91 (0.67-1.25) .56 NA NA
Missing 53 0.90 (0.55-1.45) .65 NA NA
RECIST
Stable 1147 1 [Reference] NA 1 [Reference] NA
Progressive disease 24 1.81 (1.12-2.93) .02 1.55 (0.93-2.56) .09
Partial or complete response 506 0.72 (0.61-0.85) <.001 0.80 (0.67-0.96) .02
CA 19-9 at restaging, U/mL
≥37 696 1 [Reference] NA 1 [Reference] NA
<37 (normal[ization]) 743 0.76 (0.65-0.88) <.001 0.89 (0.76-1.04) .15
Missing 238 0.82 (0.66-1.02) .07 1.03 (0.80-1.33) .80
Relative CA 19-9 change
No change/increased 83 1 [Reference] NA NA NA
Decreased <87% 513 0.84 (0.61-1.16) .29 NA NA
Decreased ≥87% 424 0.70 (0.51-0.98) .04 NA NA
<37 U/mL at diagnosis 305 0.79 (0.57-1.11) .18 NA NA
Missing 352 0.64 (0.46-0.90) .01 NA NA
pCR
No 1597 1 [Reference] NA 1 [Reference] NA
Yes 80 0.31 (0.19-0.52) <.001 0.46 (0.26-0.83) .009
Residual disease
R0 1225 1 [Reference] NA 1 [Reference] NA
R1-2 288 2.04 (1.72-2.41) <.001 1.67 (1.38-2.01) <.001
Unknown 164 1.28 (1.00-1.64) .05 1.54 (1.10-2.15) .01
Tumor size in histopathology, mm
≤20 620 1 [Reference] NA 1 [Reference] NA
21-40 793 1.67 (1.42-1.97) <.001 1.24 (1.03-1.49) .03
>40 216 2.24 (1.79-2.79) <.001 1.61 (1.24-2.09) <.001
Missing 48 1.90 (1.28-2.81) .001 1.20 (0.79-1.83) .40
Lymphovascular invasion
No 867 1 [Reference] NA 1 [Reference] NA
Yes 726 1.57 (1.36-1.82) <.001 1.13 (0.95-1.33) .16
Missing 84 1.33 (0.97-1.84) .08 1.20 (0.77-1.86) .42
Perineural invasion
No 493 1 [Reference] NA 1 [Reference] NA
Yes 1130 1.79 (1.51-2.13) <.001 1.22 (1.01-1.48) .04
Missing 54 1.31 (0.85-2.01) .22 0.93 (0.52-1.68) .81
Tumor differentiation
Gx 178 1 [Reference] NA 1 [Reference] NA
G1-G2 1030 1.16 (0.90-1.49) .25 1.09 (0.83-1.44) .54
G3-G4 313 1.87 (1.42-2.47) <.001 1.60 (1.19-2.16) .002
Missing 156 1.32 (0.94-1.84) .11 1.35 (0.94-1.94) .10
Lymph node status
ypN0 895 1 [Reference] NA 1 [Reference] NA
ypN1-2 782 1.90 (1.64-2.19) <.001 1.54 (1.30-1.81) <.001
Metastatic disease
M0 1191 1 [Reference] NA 1 [Reference] NA
M1 40 1.59 (1.04-2.43) .03 1.26 (0.82-1.94) .30
Mx 252 0.81 (0.65-1.01) .06 1.07 (0.81-1.41) .63
Missing 194 0.77 (0.61-0.99) .04 0.68 (0.51-0.91) .008
Major morbidity
No 1160 1 [Reference] NA 1 [Reference]
Yes 250 1.43 (1.19-1.73) <.001 1.28 (1.05-1.56) .01
Missing 267 0.87 (0.71-1.07) .19 0.65 (0.48-0.88) .005
Adjuvant chemotherapy
No 430 1 [Reference] NA 1 [Reference] NA
Yes 1098 0.60 (0.51-0.70) <.001 0.50 (0.42-0.59) <.001
Missing 149 0.79 (0.59-1.06) .12 0.69 (0.50-0.95) .02
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Abbreviations: ASA-PS, American Society of Anesthesiologists Performance Status; CA 19-9, carbohydrate antigen 19-9; HR, hazard ratio; (m)FOLFIRINOX, (modified) leucovorin calcium (folinic acid), fluorouracil, irinotecan hydrochloride, and oxaliplatin; NA, not applicable; pCR, pathological complete response; RECIST, Response Evaluation Criteria in Solid Tumors; SBRT, stereotactic body radiotherapy.

Factors Associated With pCR

Tumors located in the pancreatic head (OR, 2.51; 95% CI, 1.25-5.06), tumor size greater than 40 mm (vs ≤20 mm) on cross-sectional imaging at diagnosis (OR, 2.58; 95% CI, 1.03-6.48), conventional radiotherapy (vs no radiotherapy) (OR, 2.03; 95% CI, 1.00-4.10), stereotactic body radiation therapy (SBRT) (vs no radiotherapy) (OR, 8.91; 95% CI, 4.17-19.05), partial or complete radiologic response (vs stable disease) (OR, 13.00; 95% CI, 7.02-24.08), and serum CA 19-9 normal(ization) (vs CA 19-9 ≥37 U/mL) (OR, 3.76; 95% CI, 1.79-7.89) were associated with pCR. In contrast, preoperative multiagent chemotherapy other than (m)FOLFIRINOX (vs [m]FOLFIRINOX) (OR, 0.48; 95% CI, 0.26-0.87) was associated with not achieving pCR. See Table 4 for the logistic regression analysis.

Table 4. Logistic Regression Model for Estimating Associations Between Risk Factors and Pathological Complete Response.

Variable No. of patients (N = 1695) Univariable analysis Multivariable analysis
OR (95% CI) P value OR (95% CI) P value
Gender
Female 850 1 [Reference] NA NA NA
Male 845 1.12 (0.71-1.75) .63 NA NA
Tumor location
Body or tail 462 1 [Reference] NA 1 [Reference] NA
Head 1233 1.98 (1.08-3.63) .03 2.51 (1.25-5.06) .01
Tumor size at diagnosis, mm
≤20 376 1 [Reference] NA 1 [Reference] NA
21-40 1073 2.03 (0.99-4.17) .05 1.52 (0.69-3.33) .29
>40 246 3.61 (1.62-8.06) .002 2.58 (1.03-6.48) .04
Resectability at diagnosis
Primary resectable 424 1 [Reference] NA 1 [Reference] NA
Borderline resectable 827 3.54 (1.49-8.42) .004 1.63 (0.60-4.40) .34
Locally advanced 444 5.78 (2.40-13.91) <.001 2.31 (0.84-6.36) .10
CA 19-9 at diagnosis, U/mL
<37 307 1 [Reference] NA NA NA
≥37 to <150 331 0.99 (0.48-2.04) .98 NA NA
≥150 to <500 348 0.40 (0.16-0.99) .05 NA NA
≥500 to <1000 148 0.82 (0.31-2.16) .69 NA NA
≥1000 252 0.64 (0.27-1.53) .31 NA NA
Missing 309 1.94 (1.01-3.71) .05 NA NA
Preoperative chemotherapy
(m)FOLFIRINOX 771 1 [Reference] NA 1 [Reference] NA
Other multiagent 765 0.38 (0.22-0.64) <.001 0.48 (0.26-0.87) .02
Single agent 159 1.20 (0.62-2.32) .58 2.42 (0.99-5.92) .05
Preoperative radiotherapy
None 845 1 [Reference] NA 1 [Reference] NA
Conventional radiotherapy 448 3.75 (2.06-6.83) <.001 2.03 (1.00-4.10) .05
SBRT 402 4.07 (2.22-7.45) <.001 8.91 (4.17-19.05) <.001
Preoperative therapy duration, mo
<4 456 1 [Reference] NA 1 [Reference] NA
≥4 to <6 455 1.15 (0.55-2.39) .71 0.59 (0.24-1.46) .25
≥6 to <12 616 1.67 (0.88-3.18) .12 0.63 (0.27-2.45) .27
≥12 113 5.21 (2.46-11.03) <.001 2.13 (0.83-5.43) .12
Missing 55 1.82 (0.51-6.55) .36 0.99 (0.23-4.23) .98
RECIST
Stable disease 1165 1 [Reference] NA 1 [Reference] NA
Progressive disease 24 2.94 (0.37-23.00) .31 1.84 (0.20-17.30) .59
Partial or complete response 506 9.43 (5.45-16.31) <.001 13.00 (7.02-24.08) <.001
CA 19-9 at restaging, U/mL
≥37 709 1 [Reference] NA 1 [Reference] NA
<37 (normal[ization]) 748 3.59 (1.82-7.04) <.001 3.76 (1.79-7.89) <.001
Missing 238 8.80 (4.32-17.92) <.001 10.89 (4.73-25.06) <.001
Relative CA 19-9 change
No change or increased 86 1 [Reference] NA NA NA
Decreased <87% 521 0.74 (0.16-3.48) .70 NA NA
Decreased ≥87% 427 2.17 (0.50-9.44) .30 NA NA
<37 U/mL at diagnosis 307 2.16 (0.48-9.62) .31 NA NA
Missing 354 4.32 (1.02-18.36) .05 NA NA
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Abbreviations: CA 19-9, carbohydrate antigen 19-9; (m)FOLFIRINOX, (modified) leucovorin calcium (folinic acid), fluorouracil, irinotecan hydrochloride, and oxaliplatin; NA, not applicable; OR, odds ratio; RECIST, Response Evaluation Criteria in Solid Tumors; SBRT, stereotactic body radiotherapy.

Discussion

This retrospective, international cohort study of 1758 patients who underwent resection of pancreatic adenocarcinoma after preoperative chemo(radio)therapy demonstrated that pCR occurs in 4.8% of patients and is associated with better OS compared with patients without pCR. This finding is illustrated by the 3-fold higher 5-year RFS (64% vs 20%) and doubled 5-year OS (63% vs 30%) compared with patients without pCR. Factors associated with pCR included a tumor located in the pancreatic head, larger tumors, (m)FOLFIRINOX chemotherapy compared with other multiagent regimens, preoperative conventional radiotherapy and SBRT, partial or complete radiologic response, and normal(ized) serum CA 19-9 at restaging.

The 4.8% rate of pCR in the current international study is somewhat higher than the 4% reported by a systematic review comprising 27 prospective studies including 1129 patients with localized pancreatic adenocarcinoma.13 This finding could be explained by the more recent study period of our study because preoperative (m)FOLFIRINOX and modern radiotherapeutic modalities are probably more often used in recent years. Both (m)FOLFIRINOX and radiotherapy were associated with pCR after adjustment, whereby SBRT had a stronger association compared with conventional radiotherapy. This hypothesis is strengthened by the increasing incidence of pCR in the period 2004 to 2016, according to the National Cancer Database.14

This is the first study, to our knowledge, investigating the association between pCR and preoperative treatment strategies (ie, chemotherapy regimen and radiotherapeutic modalities) and serum CA 19-9. Previous reports have queried databases with small sample sizes or large databases with limited information about preoperative therapy and clinicopathological characteristics.10,11,14,16,20,21,40 Cloyd et al14 studied the National Cancer Database (pCR in 244 of 7902 patients [3.0%] diagnosed with localized pancreatic cancer [2004-2016]) and demonstrated that preoperative multiagent vs single-agent chemotherapy was not associated with pCR. In the current study, however, the odds of developing pCR were greater after (m)FOLFIRINOX compared with other multiagent chemotherapies. Remarkably, no difference was seen between (m)FOLFIRINOX and single-agent chemotherapy in our study. In contrast to the findings in our study, Cloyd et al11 demonstrated that the duration of preoperative therapy was associated with pCR. The absence of this association in the current study could be explained by probably a higher rate of modern, more potent preoperative therapies (eg, [m]FOLFIRINOX and SBRT). Some recent literature suggests the potential value of total neoadjuvant therapy (ie, chemotherapy followed by chemoradiotherapy) compared with chemotherapy followed by radiotherapy, chemoradiotherapy, or chemotherapy alone, possibly associated with higher rate of pCR and/or OS.17,19,41 In general, preoperative chemotherapy with radiation is associated with improved pathological outcomes (eg, higher rates of R0, negative lymph nodes, and tumor response) compared with chemotherapy alone, but this rarely translates into prolonged OS42,43 and might even be considered harmful when an arterial resection or divestment is needed during surgery.43,44 The lack of OS benefit was also seen in the current study, in which preoperative radiotherapy did not improve OS and SBRT was even independently associated with impaired OS. However, SBRT was associated with pCR. This finding seems conflicting because pCR is associated with longer OS (ie, median OS not reached; 63% 5-year OS), as reported by previous studies.14,15,17 This divergence suggests that pCR might not always reflect an optimal disease response and does not guarantee cure,45 illustrated by the 5-year RFS rate of 64% in this study. Nevertheless, the lower serum CA 19-9 level at restaging among patients with pCR and the association of normal(ized) serum CA 19-9 with pCR suggest that pCR represents both local and systemic disease responses in a substantial group of patients, leading to prolonged OS. Of note, the association of SBRT with shorter OS should be interpreted with caution because this finding is derived solely from patients who underwent a resection. Randomized clinical trials are necessary to determine the value of additional radiotherapy.46

The 5-year OS was doubled in patients with pCR compared with those without pCR in this study (63% vs 30%). Therefore, it is clear that pCR cannot be interpreted as synonymous with cure, also considering the 5-year RFS of 64%. Serum CA 19-9 response for prognostication and clinical decision-making in patients with pCR seems crucial because it might be a surrogate marker for the systemic disease response.47,48 Only 35% of patients with pCR received adjuvant chemotherapy compared with 67% of patients without pCR. Certain patients with pCR may benefit from additional systemic chemotherapy. However, the remaining micrometastases might have different genetic or molecular characteristics compared with the primary tumor, which might be responsible for other chemosensitivity or chemotherapy resistance.49 Better tumor markers are needed to detect the presence of remaining systemic disease.46

Reliable pathological assessment is a major concern. Recently, the International Study Group of Pancreatic Pathologists12 found moderate correlations of 0.66 and 0.71 for tumor regression grading among 23 world-leading pancreatic pathologists, using the College of American Pathologists and MD Anderson Cancer Center classification systems.28 Eight of 50 patients were classified as having pCR by at least 1 pathologist, but consensus was reached in none of the cases.28 Furthermore, variation exists among pathologists in the sampling strategy, varying from complete specimen sampling to macroscopy-based tumor sampling.30 Because pancreatic adenocarcinoma is characterized by irregular distribution of tumor cells embedded in stroma and fibrosis (ie, intratumor heterogeneity), vital tumor cells can be easily missed when the specimen is not fully sampled, particularly when the distance between vital cells further increases due to preoperative chemotherapy.30 These limitations affect the reliability of the diagnosis of pCR and could have contributed to the variability of pCR incidence per center in this study (median [IQR], 3.8% [0.3%-7.8%]). Unfortunately, the retrospective nature of the current study prohibited reliable data collection regarding the sampling strategies. Even though it is not unlikely that the pCR group in this study also contains patients with vital tumor cells left in the resected pancreas specimen, the associated prolonged OS suggests the presence of at least extensive tumor response.

Strengths and Limitations

This study has several strengths. The major strength is the large number of patients originating from multiple countries and continents (see eAppendix 7 in Supplement 1 for region-specific data) and having detailed data on treatment and disease characteristics. Furthermore, most patients were treated with modern preoperative regimens, reflecting the current clinical practices. Of note, one-quarter of the included patients were diagnosed with a primary resectable tumor, possibly treated with neoadjuvant therapy in the setting of clinical trials because neoadjuvant therapy was generally not the standard of care during the study period.50,51,52

Future research should focus on improving tumor response scoring systems. Artificial intelligence models have the potential to accurately and objectively determine residual tumor burden.53 Such models need to be further developed and validated. For now, pancreatic pathologists should strive for a uniform strategy for sampling and response evaluation. Nevertheless, the patient does not die because of what the surgeon takes out but rather what is left behind. Therefore, there is an urgent need for better markers (eg, solid, liquid, and imaging based),54,55,56 allowing more adequate response evaluation, patient selection for surgery, and postoperative clinical decision-making for adjuvant therapy.46 Fluorodeoxyglucose positron emission tomography with computed tomography or magnetic resonance imaging is a promising tool to identify biological tumor response after preoperative therapy, including pCR. However, this method needs to be investigated in all-comers instead of solely surgical cohorts.57,58

The results of this study should be interpreted in light of some limitations. First, it was considered infeasible to perform a Cox proportional hazards regression analysis on OS within the cohort of patients with pCR because of the sample size and the limited number of events. Information about associated factors might elucidate in which patients pCR means a cure or requires adjuvant therapy and whether there is a difference in prognosis for pCR after preoperative chemotherapy with or without radiotherapy. Comparative subanalyses were underpowered by the small subgroups and small number of events. Second, a more detailed stratification for preoperative chemotherapy regimens was not feasible due to the number of patients with pCR. Third, a Cox proportional hazards regression analysis investigating potential factors associated with RFS was not performed because of heterogeneity in local follow-up strategies among centers. Fourth, information about patients’ race and presence of BRCA germline mutations were not collected or available, whereas these factors seem to be of relevance for the chance to achieve major pathological response.59,60 Fifth, the number of patients with R1 was relatively low (17%), which could be explained by different local protocols for which not all specimen surfaces were assessed. Sixth, serum bilirubin levels were not collected; therefore, serum CA 19-9 levels might be reactively elevated in some patients due to hyperbilirubinemia. Seventh, patients with pCR were included when preoperative pathology was suggestive of or conclusive for malignancy22 but without central review. Therefore, the diagnosis of (pancreatic) adenocarcinoma might not always have been certain.61

Conclusions

In this international, observational, multicenter cohort study, pCR was found in 4.8% of patients with resected pancreatic adenocarcinoma after chemo(radio)therapy. Although pCR does not reflect cure, it is associated with better OS. Factors associated with pCR included preoperative chemotherapy regimens, radiation, and anatomical and biological disease response, which may have implications for treatment strategies. This finding should be confirmed in prospective studies because these factors may not universally apply to all patients with pancreatic adenocarcinoma, as illustrated by the association of SBRT with impaired OS, whereas SBRT was also associated with pCR.

Supplement 1.

eAppendix 1. Incidence of pCR per Center

eAppendix 2. Surgical Details, Surgical Outcome, and Adjuvant Therapy

eAppendix 3. Histopathology

eAppendix 4. Clinicopathological and Treatment Characteristics (Row Percentages)

eAppendix 5. Overall Survival From Starting Preoperative Chemotherapy

eAppendix 6. Site of Disease Recurrence in Patients With pCR vs Without pCR

eAppendix 7. Region-Specific Data

jamanetwopen-e2417625-s001.pdf (555.8KB, pdf)
Supplement 2.

Data Sharing Statement

jamanetwopen-e2417625-s002.pdf (14.8KB, pdf)

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

eAppendix 1. Incidence of pCR per Center

eAppendix 2. Surgical Details, Surgical Outcome, and Adjuvant Therapy

eAppendix 3. Histopathology

eAppendix 4. Clinicopathological and Treatment Characteristics (Row Percentages)

eAppendix 5. Overall Survival From Starting Preoperative Chemotherapy

eAppendix 6. Site of Disease Recurrence in Patients With pCR vs Without pCR

eAppendix 7. Region-Specific Data

jamanetwopen-e2417625-s001.pdf (555.8KB, pdf)
Supplement 2.

Data Sharing Statement

jamanetwopen-e2417625-s002.pdf (14.8KB, pdf)

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