Evaluation of Adjuvant Chemotherapy Survival Outcomes Among Patients With Surgically Resected Pancreatic Carcinoma With Node-Negative Disease After Neoadjuvant Therapy

Abstract

Importance: Neoadjuvant therapy (NAT) is rarely associated with a complete histopathologic response in patients with pancreatic ductal adenocarcinoma (PDAC) but results in downstaging of regional nodal disease. Such nodal downstaging after NAT may have implications for the use of additional adjuvant therapy (AT).

Objectives: To examine the prognostic implications of AT in patients with node-negative (N0) disease after NAT and to identify factors associated with progression-free (PFS) and overall survival (OS).

Design, setting, and participants: A retrospective review was conducted using data from 2 high-volume, tertiary care academic centers (University of Pittsburgh Medical Center and the Medical College of Wisconsin). Prospectively maintained pancreatic cancer databases at both institutes were searched to identify patients with localized PDAC treated with preoperative therapy and subsequent surgical resection between 2010 and 2019, with N0 disease on final histopathology.

Exposures: Patients received NAT consisting of chemotherapy with or without concomitant neoadjuvant radiation (NART). For patients who received NART, chemotherapy regimens were gemcitabine or 5-fluoururacil based and included stereotactic body radiotherapy (SBRT) or intensity-modulated radiation therapy (IMRT) after all intended chemotherapy and approximately 4 to 5 weeks before anticipated surgery. Adjuvant therapy consisted of gemcitabine-based therapy or FOLFIRINOX; when used, adjuvant radiation was commonly administered as either SBRT or IMRT.

Main outcomes and measures: The association of AT with PFS and OS was evaluated in the overall cohort and in different subgroups. The interaction between AT and other clinicopathologic variables was examined on Cox proportional hazards regression analysis.

Results: In this cohort study, 430 consecutive patients were treated between 2010 and 2019. Patients had a mean (SD) age of 65.2 (9.4) years, and 220 (51.2%) were women. The predominant NAT was gemcitabine based (196 patients [45.6%]), with a median duration of 2.7 cycles (IQR, 1.5-3.4). Neoadjuvant radiation was administered to 279 patients (64.9%). Pancreatoduodenectomy was performed in 310 patients (72.1%), and 160 (37.2%) required concomitant vascular resection. The median lymph node yield was 26 (IQR, 19-34); perineural invasion (PNI), lymphovascular invasion (LVI), and residual positive margins (R1) were found in 254 (59.3%), 92 (22.0%), and 87 (21.1%) patients, respectively. The restricted mean OS was 5.2 years (95% CI, 4.8-5.7). On adjusted analysis, PNI, LVI, and poorly differentiated tumors were independently associated with worse PFS and OS in N0 disease after NAT, with hazard ratios (95% CIs) of 2.04 (1.43-2.92; P < .001) and 1.68 (1.14-2.48; P = .009), 1.47 (1.08-1.98; P = .01) and 1.54 (1.10-2.14; P = .01), and 1.90 (1.18-3.07; P = .008) and 1.98 (1.20-3.26; P = .008), respectively. Although AT was associated with prolonged survival in the overall cohort, the effect was reduced in patients who received NART and strengthened in patients with PNI (AT × PNI interaction: hazard ratio, 0.55 [95% CI, 0.32-0.97]; P = .04).

Conclusions and relevance: The findings of this cohort study suggest a survival benefit for AT in patients with N0 disease after NAT and surgical resection. This survival benefit may be most pronounced in patients with PNI.

Figure 1.. Kaplan-Meier Estimates of Restricted Mean Progression-Free and Overall Survival, Stratified by Receipt of Adjuvant Therapy

A, Restricted mean progression-free survival of 413 patients was 4.4 (95% CI, 3.8-4.9) vs 3.4 (95% CI, 2.8-3.8) years (P < .001) with vs without adjuvant therapy, respectively. B, Restricted mean overall survival of 419 patients was 5.4 (95% CI, 4.9-5.9) vs 4.7 (95% CI, 4.1-5.2) years (P = .009) with vs without adjuvant therapy, respectively.

Figure 2.. Kaplan-Meier Curves Evaluating Effects of Adjuvant Therapy on Progression-Free and Overall Survival in Patients With or Without Perineural Invasion

A, Progression-free survival of 168 patients without perineural invasion (PNI), with or without adjuvant therapy (AT). B, Progression-free survival of 243 patients with PNI, with or without AT. C, Overall survival of 170 patients without PNI, with or without AT. D, Overall survival of 247 patients with PNI, with or without AT.

Figure 3.. Kaplan-Meier Estimates Examining Differences in Effects of Adjuvant Therapy on Overall Survival of Patients With or Without Perineural Invasion and Receipt of Neoadjuvant Radiation

A, Restricted mean overall survival (OS) of 49 patients without perineural invasion (PNI) who did not receive neoadjuvant radiation (NART), with or without adjuvant therapy (AT) (6.8 [95% CI, 6.3-7.8] vs 5.1 [95% CI, 3.9-6.3] years; P = .09). B, Restricted mean OS of 121 patients without PNI who received NART, with or without AT (4.8 [95% CI, 3.8-5.9] vs 6.0 [95% CI, 5.1-7.0] years; P = .23). C, Restricted mean OS of 100 patients with PNI who did not receive NART, with or without AT (5.1 [95% CI, 4.3-5.9] vs 2.0 [95% CI, 1.6-2.4] years; P < .001). D, Restricted mean OS of 147 patients with PNI who received NART, with or without AT (5.1 [95% CI, 4.2-6.0] vs 3.8 [95% CI, 3.1-4.3] years; P = .02).