Impact of pathological response after neoadjuvant chemotherapy on adjuvant therapy decisions and patient outcomes in gastrointestinal cancers

Abstract Background Neoadjuvant chemotherapy (NAC) is frequently used in gastrointestinal cancers (GIC), and pathological, radiological, and tumor marker responses are assessed during and after NAC. Aim To evaluate the relationship between pathologic, radiologic, tumor marker responses and recurrence‐free survival (RFS), overall survival (OS), adjuvant chemotherapy (AC) decisions, and the impact of changing to a different AC regimen after poor response to NAC. Methods and results Medical records of GIC patients treated with NAC at Mount Sinai between 1/2012 and 12/2018 were reviewed. One hundred fifty‐six patients (58.3% male, mean age 63 years) were identified. Primary tumor sites were: 43 (27.7%) pancreas, 62 (39.7%) gastroesophageal, and 51 (32.7%) colorectal. After NAC, 31 (19.9%) patients had favorable pathologic response (FPR; defined as College of American Pathologists [CAP] score 0–1). Of 107 patients with radiological data, 59 (55.1%) had an objective response, and of 113 patients with tumor marker data, 61 (54.0%) had a ≥50% reduction post NAC. FPR, but not radiographic or serological responses, was associated with improved RFS (HR 0.28; 95% CI 0.11–0.72) and OS (HR 0.13; 95% CI 0.2–0.94). Changing to a different AC regimen from initial NAC, among all patients and specifically among those with unfavorable pathological response (UPR; defined as CAP score 2–3) after NAC, was not associated with improved RFS or OS. Conclusions GIC patients with FPR after NAC experienced significant improvements in RFS and OS. Patients with UPR did not benefit from changing AC. Prospective studies to better understand the role of pathological response in AC decisions and outcomes in GIC patients are needed.


| INTRODUCTION
Over the last decade, there has been an increasing interest in the use of neoadjuvant chemotherapy (NAC) in patients with gastrointestinal cancers (GIC). NAC has emerged as an attractive option in both borderline resectable and resectable disease due to its potential benefits, including improved margin-negative resection rates, tumor downstaging, decreased lymph node positivity, early treatment of presumed micrometastatic disease, and improved delivery and tolerance of chemotherapy that is not hindered by postoperative complications. [1][2][3][4][5] As NAC is utilized more frequently, it is crucial to identify factors predictive of improved survival and recognize patients who are at greatest risk for recurrence.
Currently, pathological, radiological, and tumor marker responses are routinely assessed during and after neoadjuvant therapy, and our understanding of the role of pathological response, in particular, on patient outcomes is evolving. Similar to other malignancies in which achieving pathological complete response (pCR) after NAC is associated with better overall and disease-free survival, pCR in GIC typically corresponds with improved outcomes. [6][7][8] For instance, pCR after NAC has been shown to improve long-term survival in patients with esophageal, 9,10 colon, 11 and rectal 12 cancers. While the rate of pCR is relatively low in pancreatic cancer, making it difficult to assess the impact on survival, 13 studies have also reported an association with significantly prolonged survival. 14,15 On the other hand, unfavorable pathological treatment

| Patients
Institutional review board approval was obtained to review the medical records of consecutive patients with GIC, including pancreatic, gastroesophageal, and colorectal cancers, who received NAC followed by surgery between January 2012 and December 2018 at the Mount Sinai Hospital. Patients with biopsy proven pancreatic, gastroesophageal, and colorectal adenocarcinomas who underwent NAC and surgical resection were included. Though neoadjuvant radiation therapy (RT) was allowed after NAC, patients who underwent concurrent chemotherapy and radiation alone were excluded. Patients with squamous cell carcinoma were excluded.

| Data collection
Demographic and clinical data including cancer stage, systemic and locoregional therapies, pathological response, radiographic and tumor marker results, recurrence, and vital status were collected.
Post-surgical specimens were assessed with CAP protocols for tumor, margin, and nodal (TNM) assessment. 16

| Statistical analysis
Descriptive statistics were calculated to summarize baseline characteristics, including demographics, disease characteristics, and treatment characteristics. Recurrence-free survival (RFS) was measured from date of resection until detection of local recurrence, metastases, or death. Overall survival (OS) was measured from start date of NAC until death. Kaplan-Meier curves were used to estimate the median follow-up time, RFS and OS. Univariable and multivariable Cox proportional hazards models were fitted to identify predictors of RFS and OS. Variables that were significant in the univariable models were added to the multivariable models. In addition to identifying predictors of RFS and OS in the overall GIC cohort, we also performed the analyses in each of the cancer subtype cohorts. Univariable and multivariable logistic regression were fitted to identify the predictors of changing AC. p Values of less than .05 were considered to be statistically significant and hazard ratios and odds ratios with 95% confidence intervals were provided. Statistical analyses were performed using R 3.6.3 (Vienna, Austria).
In univariable analysis, FPR was associated with improved RFS (HR 0.26; 95% CI 0.10-0.64), and improved OS (HR 0.11; 95% CI 0.02-0.83), but radiographic response and ≥50% tumor marker response were not significantly associated with RFS and OS (Table 2). Additionally, given the relatively even distribution of patients with a CAP score 3 (54.5%) vs 0-2 (45.5%) in our cohort, we further analyzed the associations between these two groups.
CAP score 3 was associated with decreased RFS (HR 1.89; 95% CI Two-and five-year RFS and OS were significantly higher in patients with FPR vs UPR and in patients with CAP 0-2 vs 3 ( Figure 1).
In patients with available radiographic data, the 2-and 5-year RFS and OS in those with complete or partial radiographic response vs no response did not differ significantly (Figure 2A,B). Likewise, in patients with available tumor marker data, there were no significant differences in 2-and 5-year RFS and OS in those with ≥50% reduction in tumor markers vs no reduction ( Figure 2C,D).

| Predictors of recurrence and survival in patients with a UPR
We assessed how predictive factors affected outcomes in patients with UPR. In multivariable analysis, advanced pathological stage (4 vs 0-3) and positive surgical margins were associated with reduced RFS and OS in patients with UPR (

| Predictors of changing adjuvant therapy
We were also interested in understanding factors associated with changing AC after NAC and surgery. Though radiographic and serological responses are routinely monitored with NAC, evidence supporting their predictive role in terms of resectability and outcomes among GIC is limited. For instance, in pancreas cancer, structural imaging has significant limitations in the evaluation of treatment with chemotherapy/radiotherapy as CT and MRI cannot distinguish residual or necrotic tumor from fibrosis and radiation changes after treatment. 21 A recent study from the Mayo Clinic suggests that complete metabolic response by PET imaging highly correlates with major pathological response among patients with pancreas cancer who underwent total neoadjuvant therapy, 22 suggesting further evaluation of metabolic imaging is warranted in this setting.
Additionally, the value of tumor marker response after NAC varies among GIC. CEA clearance pattern has proven to be independent predictor of tumor response to neoadjuvant treatment in patients with rectal cancer. 23 In contrast, CA 19-9 response in pancreas cancer is unlikely a sole indicator of response, though has demonstrated association with R0 resection rate, pathological response, and survival. 24 Moreover, the optimal cut-off point for CA 19-9 "response" remains unknown. Prior reports suggest that a minimal decrease of 50% during NAC is associated with R0 resection rate and survival, yet other studies report that normalization of CA 19-9 is correlated with optimal survival. 22,24,25 Our study demonstrates that pathologic response predicts RFS and OS, which is also supported by literature across GI cancers. Complete pathologic response after NAC has been shown to significantly improve long-term survival in patients with esophageal cancer 9,10 and colon cancer. 11 Complete pathologic response in pancreatic cancer is rare, 26 but a few studies have reported an association with significantly prolonged survival. 14,15 Patients with complete pathologic response after chemoradiation have also been reported to have better long-term outcomes in rectal cancer. 12,27,28 The majority of studies to date have focused on complete pathological response (CAP score of 0) and occasionally CAP score of 1, yet the relationship between CAP score of 2 and patient outcomes remains ambiguous, despite its frequency in the real-world setting.
We therefore assessed whether outcomes differed when CAP As NAC becomes more common, prospective data will be essential to understand the role of pathological response and AC decisions on patient outcomes among GIC. In our cohort of pancreatic, gastroesophageal, and colorectal cancer patients, pathologic response was associated with changes in AC, but no RFS or OS benefit was observed among those who changed AC due to UPR after NAC. Prospective interventional studies examining the role of pathological treatment response after NAC and subsequent AC decisions among specific GI cancer cohorts are needed.