Neoadjuvant Chemotherapy and Radiation Improves Recurrence-free and Overall Survival in Resectable and Borderline Resectable Pancreatic Ductal Adenocarcinoma

Abstract

Objective

The objective of this study is to analyze the outcomes of patients with resectable/borderline resectable PDAC who receive total neoadjuvant therapy vs upfront surgery.

Methods and Analysis

Patients who were treated at a single institution from 2006 to 2021 were included. The primary outcome was overall survival (OS). Secondary outcomes included disease free survival (DFS), rates of lymph node positivity, and R0 resection. All survival analyses were performed with intention-to-treat.

Results

26 patients received neoadjuvant chemotherapy and radiation (TNT), 28 received neoadjuvant chemotherapy only (NAC), and 168 received upfront surgery. Demographics were comparable across all three groups. Patients who received TNT or NAC had longer OS and DFS compared to the surgery first patients (P < .01). Patients who received TNT had a lymph node positivity rate of 0% at time of surgery compared to 5.3% and 13.3% in the NAC and surgery-first groups, respectively (P < .01). The rate of R0 resection did not differ between groups (P = .17).

Conclusion

Patients with resectable/borderline resectable PDAC who receive neoadjuvant therapy have longer OS and RFS relative to those who receive upfront surgery.

Keywords

pancreaticoduodenectomy pancreatectomy neoadjuvant therapy

Introduction

Pancreatic adenocarcinoma (PDAC) is the second most common gastrointestinal malignancy and eleventh most common malignancy in the United States. Despite its relatively low incidence, PDAC accounts for the third most cancer deaths in the United States and has a 5-year survival rate of 6.5-20%.^1-3 It is projected to be the second leading cause of cancer-related death by 2030. As there are no good screening strategies for PDAC and a lack of early-onset clinical symptoms and signs, PDAC is often diagnosed at an advanced stage. Only 15-20% of patients are amenable for potentially curative resection at presentation.¹ Newer multiagent chemotherapy regimens have shown improved survival in patients with advanced disease.^4,5 Upon diagnosis of PDAC, patients without distant metastases are categorized into resectable, borderline resectable, or locally advanced disease.

Surgical resection is the only curative intervention for patients with resectable PDAC. However, the 5-year overall survival for resected patients remains poor at 20 to 25% currently. Therefore, upfront surgical resection is often followed by six months of adjuvant chemotherapy with either mFOLFIRNOX (Folinic Acid, 5-Fluoro Uracil, Irinotecan, and Oxaliplatin; based on PRODIGE-24 phase III trial results⁶) or Gemcitabine and Capecitabine (based on ESPAC-4 study results⁷). Chemoradiation can be administered after adjuvant chemotherapy in select patients with high-risk features such as positive/close margins (R1 resection) and/or with lymph node involvement.⁸ However, nearly 60% of PDAC patients do not receive optimal adjuvant chemotherapy because of prolonged postoperative recovery due to surgical complications or their debilitated state. Approximately 26-38% do not receive any adjuvant chemotherapy at all.^9,10

Another challenging aspect of PDAC is the high rate of postoperative early systemic progression. Recent developments in improved surgical techniques and postoperative care have translated to better perioperative outcomes and decreased local recurrence rates.⁶ Despite these advances, the 5-year mortality rate of patients who have undergone successful resection has not significantly improved over the last 20 years.⁹ Neoadjuvant therapy has been proposed to have several advantages in resectable and borderline resectable PDAC compared to adjuvant therapy recently. These include improved rates of patient tolerance and completion of systemic therapy, micrometastatic disease control, and tumor downstaging. This approach has the theoretical advantage of selecting surgery for PDAC patients with better biology and truly localized disease status.

The aim of this study is to examine the outcomes of patients with resectable or borderline resectable PDAC who received neoadjuvant treatment compared to patients who underwent surgical resection with or without adjuvant therapy. We hypothesize that patients who received neoadjuvant therapy will have improved survival compared to those that undergo upfront resection.

Materials and Methods

A retrospective chart review on all patients with resectable or borderline PDAC who were treated at a single tertiary care center between the years of 2006 and 2021 was conducted. We excluded patients who were younger than 18 years old, had stage IV disease, or had history of a second malignancy. Patients with insufficient data/follow up were also excluded. Patients were grouped by their treatment sequence: (1) surgery first followed by adjuvant therapy (surgery first group), (2) neoadjuvant chemotherapy (NAC; includes at least 3 months of chemotherapy), or (3) total neoadjuvant therapy (TNT; includes at least 3 months of chemotherapy, followed by long course (28 days) chemoradiation). Patients who did not complete at least three months of neoadjuvant chemotherapy were included within the surgery first group.

Data abstracted from the electronic medical records include demographics, tumor characteristics, surgery details, treatment course, pathology data, information on recurrence, and survival status. The primary outcome was overall survival (defined as time from date of surgery to date of death or last follow-up if still alive). Secondary outcomes were R0 resection rate, complete pathologic response rate (defined as having no pathologic evidence of cancer in resected specimen), lymph node positivity rate, and recurrence-free survival (defined as time from date of surgery to date of recurrence or last follow-up if still alive and without recurrence). Overall survival, recurrence-free survival, and R0 resection frequency were stratified by the resectability classification of the PDAC (resectable vs borderline resectable). All survival analyses were performed based on intention to treat. The institutional review board approved this study protocol.

Summary statistics were calculated. Continuous variables are described using means (±SD) or medians (IQR: 25^th, 75^th percentile) depending on normality of data. Categorical data is described using count (percentages). Categorical comparisons between groups for secondary endpoints were performed using Chi-Square or Fisher’s exact test depending on if more than 20% of the expected cell counts were less than five. Numeric endpoints were analyzed using One-Way ANOVA or Kruskal Wallis analysis depending on assumptions being met. When stratifying the categorical outcomes like overall mortality by resectability for the groups a Cochran-Mantel-Hanenszel test was used. To assess time to event analyses like mortality and recurrence, Kaplan Meier curves were generated and log-rank test statistics were ran using Tukey-Kramer corrections in pairwise comparisons. Statistical significance was set at an alpha of .05 and all P-values reported are two-tailed. All statistical analyses were completed using SAS Enterprise Guide Software, Version 7.1, SAS Institute Inc, Cary, NC.

Results

A total of 396 patients were diagnosed with PDAC over the study period and 222 patients met inclusion and exclusion criteria. Out of these 222 patients, 26 received TNT, 28 received NAC, and 168 received upfront surgery. The average patient age of all patients was 68.1 ± 10.5 years, with most patients being male (55.4%) and white (90.5%). The average BMI was 25.9 ± 5.3. Table 1 summarizes the baseline clinical characteristics of the study population. Patient demographics, comorbidities, and functional status were comparable across all three groups. There was a statistically significant difference in tumor location among the three groups (P = .02). Pairwise analysis demonstrated that the significant difference exists between the surgery first and the NAC groups (P = .01). More patients in the surgery first group had tumors in the pancreatic head than patients in the NAC group (69.0% vs 60.7%), and more patients in the NAC group having tumors in the pancreatic neck than their counterparts in the surgery first group (14.3% vs 1.2%). There was not a significant difference in tumor location between TNT and NAC groups, nor TNT and surgery first groups. Biliary obstruction at the time of diagnosis was comparable in all groups (TNT 46.1% vs NAC 64.3% vs surgery first 57.7%, P = .39). The CA 19-9 level at diagnosis was also comparable in the TNT, NAC, and surgery first groups (185 vs 104 vs 110, respectively, P = .98).

Table 1.

Patient Demographics.

Variable	Overall Patients (N = 222)	Surgery First (N = 168)	NAC (N = 28)	TNT (N = 26)	P-value
Age (years)	68.1 ± 10.5	69.0 ± 10.6	65.7 ± 9	64.9 ± 10.6	.07
Gender (male)	123 (55.4)	90 (53.6)	20 (71.4)	13 (50.0)	.18
Race
White	201 (90.5)	151 (89.9)	26 (92.9)	24 (92.3)	1.00
Black	9 (4.1)	7 (4.2)	1 (3.55)	1 (3.85)
Hispanic	8 (3.6)	6 (3.6)	1 (3.55)	1 (3.85)
Asian	1 (.45)	1 (.6)	0 (.0)	0 (.0)
Not Reported/Unknown	3 (1.35)	3 (1.8)	0 (.0)	0 (.0)
Ethnicity
Non-Hispanic	200 (90.1)	150 (89.3)	26 (92.9)	24 (92.3)	1.00
Hispanic	8 (3.6)	6 (3.6)	1 (3.57)	1 (3.85)
Unknown	13 (5.9)	11 (6.55)	1 (3.57)	1 (3.85)
Patient Refused	1 (.4)	1 (.6)	0 (.0)	0 (.0)
BMI	25.9 ± 5.3	26.2 ± 5.2	24.8 ± 5.4	25.6 ± 6.2	.45
ECOG score
0	67 (33.7)	54 (36.25)	6 (23)	7 (29.17)	.14
1	104 (52.3)	78 (52.35)	14 (53.9)	12 (50)
2	26 (13.1)	17 (11.4)	5 (19.2)	4 (16.7)
3	2 (1.0)	0 (.0)	1 (3.9)	1 (4.17)
Myocardial infarction	20 (9)	15 (8.9)	2 (7.1)	3 (11.5)	.85
CHF	16 (7.2)	11 (6.5)	3 (10.7)	2 (7.7)	.61
PVD	9 (4.1)	8 (4.8)	0 (.0)	1 (3.9)	.72
Dementia	3 (1.3)	3 (1.8)	0 (.0)	0 (.0)	1.00
COPD	21 (9.5)	18 (10.7)	1 (3.6)	2 (7.7)	.59
Peptic ulcer disease	7 (3.2)	5 (3.0)	1 (3.6)	1 (3.9)	.83
Cirrhosis (class A)	2 (.9)	2 (1.2)	0 (.0)	0 (.0)	1.00
Diabetes no complications	65 (29.3)	49 (29.2)	7 (25)	9 (34.6)	.74
Diabetes with complications	12 (5.4)	9 (5.4)	1 (3.6)	2 (7.7)	.77
ESRD	4 (1.8)	4 (2.4)	0 (.0)	0 (.0)	1.00
Leukemia	4 (1.8)	3 (1.8)	0 (.0)	1 (3.9)	.45
Lymphoma	3 (1.35)	3 (1.8)	0 (.0)	0 (.0)	1.00
Immunosuppression	1 (.45)	1 (.6)	0 (.0)	0 (.0)	1.00

NAC: neoadjuvant chemotherapy group; TNT: total neoadjuvant therapy group; BMI: body mass index; ECOG: Eastern Cooperative Oncology Group; CHF: congestive heart failure; PVD: peripheral vascular disease; COPD: chronic obstructive pulmonary disease; ESRD: end stage renal disease.

Patients who received neoadjuvant treatment most commonly received either FOLFIRINOX or gemcitabine and nab-Paclitaxel. In the TNT group, FOLFIRINOX was prescribed to 73.1% of patients and Gemcitabine/nab-Paclitaxel were prescribed to 19.2%. In the NAC group, FOLFIRINOX was prescribed to 67.9% of patients and Gemcitabine/nab-Paclitaxel were prescribed to 21.4% of patients. Of patients who received TNT, 88.5% were able to undergo surgical resection of the primary tumor, compared to 82.1% of patients who received NAC. At the time of surgery, median tumor size was similar among all groups (TNT 3.0 vs NAC 3.2 cm vs surgery first 3.3 cm, P = .84). Patients with TNT had a resected lymph node positivity rate of .0%, whereas those with NAC or surgery first had a positivity rate of 5.3% and 13.3%, respectively (P < .01). The rate of R0 resection was comparable amongst all three groups (TNT 82.6% vs NAC 73.9% vs surgery first 64.3%, P = .17). When stratifying by tumor resectability (resectable vs borderline resectable), TNT, NAC, and surgery first groups continued to have comparable rates of R0 resection (P = .12). For those with borderline resectable PDAC, the rates of R0 resection for TNT, NAC, and surgery first groups are 80%, 81.8%, and 58.3%, respectively. Two patients with TNT had complete pathologic response at time of surgery, whereas no patients who received NAC or surgery first had complete pathologic response (P = .02). Pairwise analysis demonstrated a statistically significant difference in complete pathologic response between TNT and surgery first (P = .01); there was no statistically significant difference between TNT and NAC (P = .49). Please see Table 2 for all treatment-specific variables that were analyzed.

Table 2.

Treatment-specific Variables.

Variable	Overall Patients (N = 222)	Surgery First (N = 168)	NAC (N = 28)	TNT (N = 26)	P-value
Tumor location
Pancreatic head	147 (66.2)	116 (69)	17 (60.7)	14 (53.85)	.02
Uncinate process	8 (3.6)	7 (4.2)	0 (0)	1 (3.85)
Pancreatic neck	8 (3.6)	2 (1.2)	4 (14.3)	2 (7.7)
Pancreatic body/tail	59 (26.6)	43 (25.6)	7 (25)	9 (34.6)
Biliary obstruction at diagnosis	127 (57.2)	97 (57.7)	18 (64.3)	12 (46.1)	.39
CA 19-9 level at diagnosis	110.3 [26.3, 378.2]	110.3 [24.8, 469.3]	104 [28, 355]	185 [30.9, 330]	.98
Resectability
Resectable	179 (81)	156 (92.9)	15 (53.6)	8 (32)	<.01
Borderline resectable	42 (19)	12 (7.1)	13 (46.4)	17 (68)
Tumor size	3.2 [2.5, 4.5]	3.3 [2.5, 4.5]	3.2 [1.5, 5]	3 [1.8, 7]	.84
Lymph nodes positivity rate (%)	10.5 [0, 26.3]	13.3 [0, 30.8]	5.3 [0, 14.3]	0 [0, 6.7]	<.01
Underwent neoadjuvant therapy, never had surgery	NA	NA	5 (17.9)	3 (11.5)	.71
Complete RO resection	144 (67.3)	108 (64.3)	17 (73.9)	19 (82.6)	.17
Complete pathologic response	2 (.94)	0 (0)	0 (0)	2 (8.7)	.02

NAC: neoadjuvant chemotherapy group; TNT: total neoadjuvant therapy group.

Following surgery, only 41.7% of patients (n = 70) in the surgery first group received both adjuvant chemotherapy and radiation, while 23.8% (n = 40) received only adjuvant chemotherapy and 3.6% (n = 6) received adjuvant radiation alone. The remaining patients (n = 52, 30.9%) did not receive any adjuvant therapy. The mean recurrence free survivals (RFS) of the TNT, NAC, and surgery first groups were 17.5, 25.7, and 16.3 months, respectively (P < .01). Pairwise analysis demonstrates that there is a statistically significant difference between surgery first and TNT (P < .01), as well as surgery first and NAC groups (P < .01). The 3-year RFS probability curve for all groups is shown in Figure 1.

Patients who received TNT or NAC had improved overall survival compared to the surgery first group (TNT vs surgery first P < .01, NAC vs surgery first P < .01). At one year, patients with TNT, NAC, and surgery first had 96.0%, 88.7%, and 66.3% survival, respectively, and at three years they had 65.6%, 49.2%, and 28.0% survival, respectively (Figure 2). The two patients who achieved complete pathologic response following TNT remain alive and without disease recurrence.

Discussion

In our study, most patients who had resectable disease at time of diagnosis underwent surgery first (87.2%), whereas patients who had borderline resectable PDAC received neoadjuvant treatment (71.4%). The neoadjuvant chemotherapy regimen was chosen based on the patient’s ECOG performance status. Patients with a higher performance status received FOLFIRINOX whereas those with a lower performance status tended to receive gemcitabine-based therapy. Unlike those in the surgery first group, all patients in the neoadjuvant therapy group were found to complete chemotherapy. This adds further support to the argument that the administration of chemotherapy prior to surgery results in improved completion rates of systemic treatment.

While neoadjuvant therapy increases the chances of completing systemic treatment, there is also risk that disease progression will prohibit the patient from receiving resection in the future, which is the only curative treatment. ¹¹ In our study, 14.8% of patients who received neoadjuvant therapy did not proceed with operative resection secondary to disease progression and declining functional status, indicating an aggressive form of disease. Neoadjuvant therapy can therefore allow for patients with an aggressive disease to self-select during this time and potentially be “spared” the morbidity and mortality associated with pancreatectomy.

Neoadjuvant therapy has not only increased the rates of chemotherapy completion in patients with resectable and borderline resectable PDAC, but evidence also suggests improved surgical outcomes in patients treated with neoadjuvant chemotherapy (NAC) alone or in combination with radiation (TNT).^3,12 NAC and TNT are hypothesized to decrease tumor size and treat micrometastatic disease, which may result in higher rates of successful surgical resection and lower rates of lymph node positivity. Our study supports this hypothesis. While the rates of R0 resection were comparable in the TNT, NAC, and surgery first groups (82.6% vs 73.9% vs 64.3%, respectively), patients receiving TNT or NAC did have increased rates of R0 resection relative to their counterparts in the surgery first group. In addition, patients in the TNT and NAC groups were shown to have decreased rates of lymph node positivity compared to upfront surgery with rates of 0%, 5.3%, and 13.3%, respectively. These findings support those of the ESPAC-5 study.¹³ Improved locoregional control with neoadjuvant therapy may reduce the patient’s risk of disease recurrence, which is notoriously high for PDAC.

Few studies have demonstrated an improved overall survival in patients receiving neoadjuvant chemotherapy for treatment of PDAC,^3,14,15 even with the addition of chemoradiation.^16,17 Our data, however, demonstrates a statistically significant difference in survival between the neoadjuvant therapy group and surgery first group. The reason for improved survival in patients receiving either TNT or NAC is likely multifactorial. These factors include, quicker time to initiation of systemic therapy, higher likelihood of systemic therapy completion, “weeding” out those that would not benefit from surgery due to aggressive biology of tumor and/or poor functional status.

Several studies are investigating the use of peri-operative chemotherapy (given in both the neoadjuvant and adjuvant settings) and comparing it to adjuvant chemotherapy alone in patients with resectable PDAC. NEONAX is a phase II trial comparing 8 weeks of neoadjuvant gemcitabine/nab-paclitaxel followed by surgery and 16 weeks of adjuvant gemcitabine/nab-paclitaxel to surgery with 24 weeks of adjuvant gemcitabine/nab-paclitaxel (NCT02047513). NEONAX has completed recruitment, and no results have been posted as of yet. PREOPANC-3 is a multi-centered study investigating the role of perioperative mFOLFIRINOX chemotherapy (8 neoadjuvant cycles followed by surgery and 4 adjuvant cycles) and surgery compared to upfront surgery followed by 12 cycles of adjuvant mFOLFIRINOX (NCT04927780). Recruitment is ongoing and the study’s estimated completion date is July 2029. Another large phase III trial is also evaluating perioperative mFOLFIRINOX and comparing it to adjuvant chemotherapy (NCT04340141). Perioperative chemotherapy may capture the benefits of both neoadjuvant and adjuvant chemotherapy; a shorter course of neoadjuvant therapy may be sufficient for reaping the benefits of early systemic treatment, while also getting them to the OR expeditiously for surgical resection.

There are several limitations to the current study. First, it is a retrospective study that predisposes it to selection bias. Our study period spanned the transition from paper charts to electronic medical records. As a result, some patient data were incomplete. Second, our group’s practice pattern changed where more patients were recommended to receive neoadjuvant therapy towards the end of our study period. In addition, several patients have been lost to follow-up. The results of the study therefore should be interpreted with these limitations in mind.

In conclusion, our study shows that patients with PDAC who receive neoadjuvant chemotherapy, with or without radiation, are more likely to complete systemic therapy in comparison to surgery cohort. Those who received neoadjuvant therapy had improved locoregional control and showed a survival advantage (OS and DFS) compared to those who underwent surgery first. Larger prospective studies are needed to confirm our findings.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Jesse K. Kelley

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