Prognostic Impact of a Decrease in Serum Carbohydrate Antigen 19-9 Levels After Preoperative Therapy for 4 Months or More for Borderline Resectable Pancreatic Cancer Abutting Major Arteries

Abstract

Background: This study aimed to identify the prognostic factors after pancreatectomy for borderline resectable pancreatic cancer abutting major arteries (BR-A).

Methods: We retrospectively investigated relationship between preoperative and intraoperative variables and overall survival (OS) through univariate and multivariate analyses. The cut-off points of preoperative therapy duration and response rates of serum carbohydrate antigen 19-9 (CA19-9) levels after preoperative therapy were determined through a minimum P-value approach using the log-rank test for OS. Overall survival was compared among patients stratified according to the independent prognostic factors and the presence or absence of pancreatectomy.

Results: After pretreatment, 17 patients underwent pancreatectomy and four patients continued chemotherapy without surgery. Multivariate analysis in 17 resected BR-A patients demonstrated decreased serum CA19-9 levels and preoperative therapy duration of ≥4 months were the independent prognostic factors [hazard ratio (HR) 0.01; P = 0.002, HR 0.13; P = 0.02]. Patients who underwent surgery with decreased serum CA19-9 levels after preoperative therapy of ≥4 months had a significantly better prognosis than those without one or both of independent prognostic factors and those who did not undergo surgery (median survival time: not estimated, 23.3 months, 10.5 months, and 10.8 months; P = 0.02, P = 0.004, and P = 0.001, respectively). Furthermore, the prognosis did not significantly differ between the patients who underwent surgery without meeting either one or both criteria and those without surgery.

Conclusions: Preoperative therapy duration of ≥4 months and decreased serum CA19-9 levels are independent prognostic factors among BR-A patients.

Keywords

borderline resectable pancreatic cancer pancreatectomy neoadjuvant therapy overall survival

Key Takeaways

• We evaluated the prognostic factors after pancreatectomy for borderline resectable pancreatic cancer abutting major arteries (BR-A).

• Decreased serum CA19-9 levels and preoperative therapy duration of ≥4 months could be prognostic predictors of resected BR-A pancreatic cancer.

• Among the patients with preoperative therapy duration of ≥4 months, the number of patients with ≥grade IIb according to the Evans classification was significantly higher.

Introduction

Pancreatic cancer (PC) is a very malignant disease with a poor prognosis.¹ Surgical resection is the only chance of cure. However, only 20%-30% of patients diagnosed with PC undergo curative resection,^2,3 and the postoperative 5-year survival rate after radical resection is only approximately 20%.⁴

Borderline resectable (BR) PC represents tumors at high risk for positive surgical margins after radical resection.⁵ The National Comprehensive Cancer Network (NCCN) guidelines classifies BRPC into two categories, BRPC invading the portal vein (BR-PV) and BRPC abutting major arteries (BR-A).⁶ A recent consensus stated that BRPC should be treated with neoadjuvant therapy (NAT) followed by resection and adjuvant therapy.⁷ This strategy makes sense, as the reduction in tumor size leads to R0 resection and patient selection leads to fewer recurrences due to distant occult metastases. However, the prognostic factors, including the surgical timing and optimal duration of preoperative therapy for BRPC, remain controversial. The present study aimed to identify the prognostic factors after pancreatectomy for BR-A, including the optimal duration of preoperative therapy.

Methods

Patients

This study retrospectively reviewed the medical records of 20 consecutive BR-A patients. Among the 20 patients, 16 underwent pancreatectomy for BR-A following preoperative therapy at Jikei University Hospital, Jikei University Daisan Hospital and Saku Central Hospital Advanced Care Center from 2015 to 2022. The remaining 4 patients received chemotherapy without surgery at Jikei University Hospital from 2017 to 2019. This study was approved by the Ethics Committee of the Jikei University School of Medicine (27-177 [8062]).

Treatment Strategy

The patients were preoperatively diagnosed by dynamic computed tomography to categorize them as patients with BR-A according to the NCCN guidelines⁶ during a multidisciplinary team meeting.

The patients received chemotherapy with gemcitabine plus nab-paclitaxel (GnP), gemcitabine plus S-1 (GS), or S-1 plus radiation after GnP regimen, which was selected based on patient age, general condition, and individual doctor’s opinion. The study inclusion criteria for surgery were initially as follows: patients with partial response and stable disease defined by the Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1,⁸ following preoperative therapy and expected to undergo R0 resection.

We retrospectively reviewed a prospectively maintained database of patients histologically diagnosed with PC. The pathological findings and tumor stage were based on the general rules of the 8th edition of the Union for International Cancer Control tumor, node, and metastasis classification system.⁹ The pathological parameters included residual tumor grading and Evans classification.¹⁰

First, we investigated the relationship between preoperative and intraoperative variables and overall survival (OS) in patients who underwent pancreatectomy through univariate and multivariate analyses. OS was defined as the time from nonsurgical anticancer therapy to death or the last follow-up date. The variables investigated included age, sex, Eastern Cooperative Oncology Group-Performance Status, tumor location, preoperative therapy duration, pretreatment and preoperative serum carbohydrate antigen 19-9 (CA19-9) levels, rate of decrease in serum CA19-9 level after preoperative therapy, pretreatment maximum tumor diameter, tumor response according to the RECIST, dissection of nerve plexus, and portal vein resection and reconstruction. The cut-off values of pretreatment serum CA19-9 levels were determined based on a previous report.¹¹ Regarding the preoperative therapy duration and response rates of serum CA19-9 levels after preoperative therapy, the log-rank test was performed to compare the data among subgroups. A minimum P-value approach was used to evaluate the optimal threshold to divide the patients into two groups based on their OS duration. In this approach, the log-rank test was performed for different OS durations to determine the optimal cut-off point with the lowest P value.

Subsequently, we investigated the relationship between the 18 clinicopathological variables, which are the 12 previously described perioperative factors and another set of 6 pathological and postoperative factors (ie, pathological maximum tumor diameter, lymph node metastasis, number of metastatic lymph nodes, curability, histological assessment of preoperative therapeutic effects according to the Evans classification, and adjuvant therapy) and the preoperative therapy duration through a univariate analysis.

Finally, we compared the OS between patients undergoing surgery and those without surgery.

Statistical Methods

Continuous data are expressed as medians and ranges and were compared between two groups using the Mann–Whitney U-test and among three groups using the Kruskal‒Wallis test. Categorical data were compared using the chi-square test. Univariate analyses of OS were performed using the log-rank test. Multivariate analysis, including all variables with P-values <0.05 in the univariate analysis, was performed using the Cox proportional hazards model. The survival curve was developed using the Kaplan‒Meier method, and differences were evaluated using the log-rank test. All P-values were considered statistically significant when the associated probability was <0.05 using Statistical Package for the Social Sciences (version 26.0 for Windows, Armonk, NY, USA).

Results

Patients’ Characteristics

The characteristics of the 17 patients, including ten men and seven women, who underwent pancreatectomy are summarized in Table 1. The patients’ median age was 70 years (range: 51-80 years). The preoperative therapy regimen in most patients was GnP (88%). The operative procedure included subtotal stomach-preserving pancreaticoduodenectomy in nine patients, and distal pancreatectomy (DP) in eight patients, with two patients undergoing DP with celiac axis resection. No microscopic residual tumor (R0) was observed in 13 (76%) patients. None died at the hospital. Twelve patients (71%) received adjuvant therapy, with S-1 (59%) being the most common adjuvant therapy regimen utilized. The median follow-up duration of the censored patients was 27.9 months (range: 16.3-99.6 months). The cut-off values of the preoperative therapy duration and response rates of serum CA19-9 after preoperative therapy were 4 months and no decrease, respectively (Figure 1). The decreased rates in serum CA19-9 levels in the group that improved after preoperative treatment were 77 (18-99) %. On the other hand, the increased rates in serum CA19-9 levels in the group that did not improve after preoperative treatment were 60 (0-409) %.

Table 1.

The Clinical Patient Characteristics According to the Preoperative Therapy Duration.

Variables	n (%) or Median (Range)	Duration of Preoperative Therapy		P-Value
		<4 Months (n = 10)	≥4 Months (n = 7)
		n (%) or Median (Range)	n (%) or Median (Range)
Age (years)	70 (51-80)	72.5 (58-80)	65 (51-72)	0.01
Sex, female	7 (41)	5 (50)	2 (29)	0.38
ECOG-PS, 1	1 (6)	0 (0)	1 (14)	0.22
Location of tumor, Ph	9 (53)	6 (60)	3 (43)	0.49
Regimen of preoperative therapy				0.53
GnP	13 (76)	8 (80)	5 (71)
GnP followed by S-1 with RT	1 (6)	0 (0)	1 (14)
GnP followed by GS	1 (6)	1 (10)	0 (0)
GS	2 (12)	1 (10)	1 (14)
Duration of preoperative therapy	3 (1-11)	2.5 (1-3)	6 (4-11)	≺0.001
Pretreatment serum CA19-9 level (U/mL)	264 (1-3986)	322 (1-3986)	264 (5-1509)	0.96
Preoperative serum CA19-9 level (U/mL)	34 (1-2459)	39 (1-2459)	29 (8-108)	0.27
Normalization of preoperative serum CA19-9 level (≤37 U/mL)	10 (59)	5 (10)	5 (71)	0.38
Decreased rates of serum CA 19-9 level (%)	76 (-409 to 99)	68 (-409 to 99)	78 (-60 to 99)	0.48
Decreased rates of serum CA 19-9 level, improved	14 (82)	8 (80)	6 (86)	0.76
Pretreatment maximum tumor diameter (mm)	27 (14-49)	27.5 (18-35)	27 (14-49)	0.96
Preoperative maximum tumor diameter (mm)	17 (12-37)	17.5 (13-37)	17 (12-30)	0.48
Tumor response by RECIST version 1.1, PR	8 (47)	4 (40)	4 (57)	0.49
Surgical procedure, PD	9 (53)	5 (50)	4 (57)	0.77
Dissection of nerve plexus, yes	9 (53)	5 (50)	4 (57)	0.77
PVR, yes	4 (24)	3 (30)	1 (14)	0.45
Pathological maximum tumor diameter (mm)	30 (8-77)	28.5 (8-77)	30 (9-50)	1.00
Lymph node metastasis, yes	10 (59)	7 (70)	3 (43)	0.26
Number of metastatic lymph nodes	1 (0-8)	1 (0-8)	0 (0-8)	0.32
Curability, R1	4 (24)	3 (30)	1 (14)	0.45
Histological assessment of preoperative therapeutic effects by Evans classification				0.15
I	6 (35)	4 (40)	2 (29)
IIa	8 (47)	6 (60)	2 (29)
IIb	2 (12)	0 (0)	2 (29)
III	1 (6)	0 (0)	1 (14)
Histological assessment of preoperative therapeutic effects by Evans classification, grade II or III	11 (65)	6 (60)	5 (71)	0.63
Histological assessment of preoperative therapeutic effects by Evans classification, grade IIb or III	3 (18)	0 (0)	3 (43)	0.02
Postoperative adjuvant therapy, yes	11 (65)	5 (50)	6 (86)	0.13
Adjuvant therapy				0.07
S-1	10 (59)	8 (57)	6 (86)
GEM	1 (6)	1 (7)	0 (0)
GEM + RT	1 (6)	1 (7)	1 (14)
None	5 (29)	4 (29)	0 (0)

ECOG-PS, Eastern Cooperative Oncology Group-Performance Status; Ph, pancreas head; GnP, gemcitabine plus nab-paclitaxel; RT, radiation therapy; GS, gemcitabine plus S-1; CA19-9, carbohydrate antigen 19-9; RECIST, Response Evaluation Criteria In Solid Tumors; PR, partial response; PD, pancreaticoduodenectomy; PVR, portal vein resection and reconstruction; GEM, gemcitabine.

Univariate and Multivariate Analyses of OS Predictors After Pancreatectomy

Table 2 shows the association between the preoperative and intraoperative variables and OS. In the univariate analysis, OS was significantly better when the preoperative therapy duration was ≥4 months (P = 0.04) and the serum CA19-9 level was decreased after preoperative therapy (P < 0.001). In the multivariate analysis, the preoperative therapy duration of ≥4 months and the decrease in preoperative serum CA19-9 levels after preoperative therapy were the independent and significant predictors of OS [hazard ratio (HR) 0.13; 95% confidence interval (CI) 0.03-0.69; P = 0.02, HR 0.01; 95% CI 0.001-0.21; P = 0.002, respectively].

Table 2.

Univariate and Multivariate Analyses of Overall Survival After Pancreatectomy Following Preoperative Therapy for Borderline Pancreatic Cancer Abutting Major Arteries.

Variables	n (%)	Univariate Analysis		Multivariate Analysis
Variables	n (%)	HR (95% CI)	P-Value	HR (95% CI)	P-Value
Age, ≥65 years	13 (76)	0.72 (0.16-2.96)	0.63
Sex, female	7 (41)	1.30 (0.36-4.93)	0.68
ECOG-PS, 1	1 (6)	0.26 (0.04-1.72)	0.16
Location of tumor, Pbt	10 (59)	1.14 (0.32-4.17)	0.83
Duration of preoperative therapy, <4 months	7 (41)	0.28 (0.07-0.86)	0.04	0.13 (0.03-0.69)	0.02
Pretreatment serum CA19-9 level, ≥500 U/mL	5 (29)	0.88 (0.25-2.99)	0.82
Normalization of preoperative serum CA19-9 level (≤37 U/mL)	10 (59)	0.78 (0.22-0.71)	0.70
Change of serum CA19-9 level, decrease	14 (82)	0.04 (0.004-0.38)	<0.001	0.01 (0.001-0.21)	0.002
Maximum tumor diameter before preoperative therapy, >30 mm	4 (25)	2.69 (0.77-17.13)	0.11
Tumor response by RECIST version 1.1, PR	8 (47)	0.88 (0.22-3.39)	0.85
Dissection of nerve plexus, yes	9 (53)	0.76 (0.21-2.52)	0.63
PVR, yes	4 (24)	1.48 (0.27-9.28)	0.61

HR, hazard ratio; CI, confidence interval; ECOG-PS, Eastern Cooperative Oncology Group-Performance Status; Pbt, pancreatic body and tail; CA19-9, carbohydrate antigen 19-9; RECIST, Response Evaluation Criteria In Solid Tumors; PR, partial response; PVR, portal vein resection and reconstruction.

Univariate Analysis of the Relationship Between the Clinicopathological Characteristics and Preoperative Therapy Duration

Table 1 shows the association between the clinicopathological variables and preoperative therapy duration. Patients with a preoperative therapy duration of ≥4 months were significantly younger than those with a preoperative therapy duration of <4 months (P = 0.01). Among the patients with preoperative therapy duration of ≥4 months, the number of patients with ≥grade IIb according to the Evans classification was significantly higher (P = 0.02).

Impact of Preoperative Therapy Duration and Serum CA19-9 Level Change After Preoperative Therapy on OS

The OS was significantly better in patients with a preoperative therapy duration of ≥4 months than in those with a preoperative therapy duration of <4 months [3-year OS rates: 53.6% vs 17.5%; median survival time (MST): not estimated (range: 18.9-99.6 months) vs 23.2 months (range: 10.5-44.8 months); HR 0.28; 95% CI 0.07-0.86; P = 0.04)] (Figure 2(a)). Overall survival was significantly better in patients with decrease in serum CA19-9 levels after preoperative therapy than in those with no decrease [3-year OS rates: 44.6% vs 0%; MST: 29.5 months (range: 11.3-99.6 months) vs 11.2 months (range: 10.5-18.9 months); HR 0.01; 95% CI 0.001-0.21; P < 0.001] (Figure 2(b)).

The OS was significantly better in patients who underwent surgery a decrease in serum CA19-9 levels after preoperative therapy of ≥4 months than in those who underwent surgery with a decrease in serum CA19-9 levels after preoperative therapy of <4 months or without a decrease in serum CA19-9 levels after preoperative therapy of ≥4 months, in those with surgery without a decrease in serum CA19-9 level after preoperative therapy of <4 months, and in those without surgery (MST not estimated, 23.3 months, 10.5 months, and 10.8 months, respectively; P = 0.02, P = 0.004, and P = 0.001, respectively). Contrarily, the OS was not significantly worse in patients without surgery than in those with surgery, except in the condition that the serum CA19-9 levels decreased after preoperative therapy ≥4 months (Figure 2(c)).

Impact of Pathological Factors and Adjuvant Therapy on OS

The OS was significantly better in patients with a tumor diameter <50 mm, with R0 resection, and with adjuvant therapy than in those with a tumor diameter ≥50 mm, with R1 resection, and without adjuvant therapy (MST 29.5 vs 11.3 months, 44.8 vs 11.2 months, and 44.8 vs 21.6 months; P = 0.03, P = 0.01, P = 0.02, respectively) (Figure 3(a),(e), and (f)). A significant prognostic improvement was observed as the grade of the Evans classification increased (P = 0.02). The OS was significantly better in patients with grade II or III disease according to the Evans classification than in those with grade I disease (MST 44.8 vs 11.3 months; P = 0.002) (Figure 3(c)). Contrarily, the OS tended to be worse in patients with lymph node metastasis than in those without (MST 21.6 vs 44.8 months; P = 0.09) (Figure 3(b)).

Discussion

In the present study, we evaluated the impact of preoperative therapy duration and changes in serum CA19-9 levels after preoperative therapy for BR-A. The results of the multivariate analysis indicated that preoperative therapy duration of ≥4 months and a decrease in serum CA19-9 levels after preoperative therapy were independent prognostic factors among patients who underwent pancreatectomy for BR-A. Patients who underwent surgery with a decrease in serum CA19-9 levels after preoperative therapy of ≥4 months had a significantly better prognosis than those who did not meet either criterion or both criteria. Furthermore, those who underwent surgery without meeting either one or both of these two criteria did not significantly differ in prognosis when compared with patients who did not undergo surgery.

The prognostic factors for patients who underwent surgery for BRPC were reported to be pretreatment serum CA19-9 level of >400,¹² or ≥500 U/mL,¹³ neoadjuvant therapy,¹³ and PNI.¹⁴ The preoperative therapy duration for BRPC has been proposed to be 10 weeks to 4 months,^11,15,16 with 6 months reported as an independent prognostic factor. This finding is based on an analysis of cases that included BR and unresectable-locally advanced PC¹⁷; however, no analysis of BRPC cases alone has been conducted. On the other hand, there is a large bias in the duration of preoperative treatment because this is a retrospective study in which each surgeon was not judged to be progressive disease by the RECIST version 1.1 for efficacy, and was technically deemed to be capable of performing radical (R0) surgery. Therefore, a minimum P-value approach was used to evaluate the optimal threshold to divide the patients into two groups based on their overall survival duration. To the best of our knowledge, we reported for the first time that a preoperative therapy duration of 4 months for BR-A is an independent prognostic factor.

No study has reported that the rate of decrease in CA19-9 levels after preoperative treatment is an independent prognostic factor for BRPC, but several studies have reported on the normalization of serum CA19-9 levels after preoperative therapy.^18-20 In the present study, the normalization of serum CA19-9 levels was not found as an independent prognostic factor, possibly because of the small number of such patients analyzed.

The present study has several limitations. First, it was a retrospective study conducted at multi-centers with a relatively small sample size. Our results should be validated in prospective studies with a larger sample size. The cut-off value for the decreased rates of serum CA19-9 levels after preoperative treatment was synonymous with no decrease with a minimum value of 18% in the reduction group. A specific value of the decreased rates of serum CA19-9 levels after preoperative treatment as a cut-off value by increasing the number of samples is desired. Second, the various preoperative therapy regimens used in this study made the evaluation of the indicated regimens difficult. In the past, many reports had no unified preoperative therapy regimen^14,18,19,21; however, reports of a single treatment with GnP plus S-1,¹⁶ GnP,^11,20 GEM plus radiation therapy (RT),¹⁵ or modified FOLFIRINOX plus RT²² have been increasing recently, and the efficacy of GEM plus RT and GnP has been reported. In the future, the effectiveness of preoperative therapy based not only on a GEM-based regimen with or without RT but also on immune checkpoint inhibitors and the results of genetic testing panels should be examined.

In conclusion, a decrease in serum CA19-9 levels after preoperative therapy of ≥4 months is necessary to improve the prognosis of patients after undergoing pancreatectomy for BR-A.

Footnotes

Author Contributions

MM, MT, YF, and TU developed the main concept and designed the study. MM, KA, YF, and SO were responsible for the acquisition of clinicopathological data. MM, KF, KH, TU, TO, and TI contributed to the clinical data analysis. MM and TI wrote the manuscript. All authors have read the manuscript and approved its submission.

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) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by the Japan Society for the Promotion of Science KAKENHI Grant Number 23K15483 (Dr Michinori Matsumoto), 21K08718 (Dr Toru Ikegami), 21K08805 (Dr Koichiro Haruki), 23K08222 (Dr Kenei Furukawa), and by research grants from the Princess Takamatsu Cancer Research Fund (Dr Ikegami).

ORCID iDs

Michinori Matsumoto

Masashi Tsunematsu

Koichiro Haruki

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