Impact of Radiological and Pathological Splenic Vein Involvement in Patients with Resectable Pancreatic Body or Tail Cancer

doi:10.21203/rs.3.rs-3231316/v1

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Research Article

Impact of Radiological and Pathological Splenic Vein Involvement in Patients with Resectable Pancreatic Body or Tail Cancer

https://doi.org/10.21203/rs.3.rs-3231316/v1

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Journal Publication

published 15 Jan, 2024

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Purpose

Several studies have reported a negative impact on survival associated with splenic vessel involvement, especially splenic artery (SpA) involvement, in patients diagnosed with pancreatic body or tail cancer. However, there is limited research on splenic vein (SpV) involvement. Therefore, we aimed to elucidate the significance of splenic vessel involvement, especially SpV involvement, in patients with resectable pancreatic body or tail cancer.

Methods

Between January 2007 and December 2021, 116 consecutive patients underwent distal pancreatectomies for pancreatic body or tail cancer. Among them, this study specifically examined 88 patients with resectable pancreatic body or tail cancer to elucidate prognostic factors using a multivariable Cox proportional analysis. The Kaplan–Meier method evaluated the impact of SpV involvement in terms of both radiological and pathological aspects and the efficacy of neoadjuvant therapy.

Results

Higher pre-operative carcinoembryonic antigen levels, larger tumour size, pathological SpV invasion, and non-completion of adjuvant therapy were identified as independent poor prognostic factors for overall survival (OS) and recurrence-free survival (RFS). Additionally, patients with radiological SpV encasement had significantly worse prognoses in terms of OS (p = 0.039) and RFS (p < 0.001). The sensitivity and specificity of multidetector-row computed tomography for detecting pathological SpV invasion were 81.0% and 61.2%, respectively. However, the prognostic impact of neoadjuvant therapy could not be determined, regardless of radiological SpV involvement.

Conclusion

Radiological and pathological SpV involvement is a poor prognostic factor for patients with resectable pancreatic body or tail cancer. New innovative treatments and effective neoadjuvant therapy regimens are required for patients with SpV involvement.

neoadjuvant therapy

pancreatic body or tail cancer

prognosis

resectable

splenic vein

Pancreatic cancer (PC) is the seventh leading cause of cancer-related deaths worldwide. Despite advancements in imaging detection, surgical techniques, and perioperative therapy for PC, the 5-year survival rate remains low at only 9% [1]. Since surgical resection represents the only curative treatment option for PC, the National Comprehensive Cancer Network (NCCN) guidelines established a resectability classification to guide surgical decisions. This classification consists of three surgical categories: resectable (R), borderline resectable (BR), and locally advanced unresectable (LA-UR) [2, 3]. It is primarily based on the degree of tumour extension into the two major vessel systems of PC: the arterial system, including the celiac axis (CA), common hepatic artery (CHA), and superior mesenteric artery (SMA), and the portal system, including the portal vein (PV) and superior mesenteric vein (SMV). However, this classification does not include the splenic artery (SpA) and vein (SpV), which are the major vessels involved in pancreatic body or tail cancer. This omission is due to the ease of resecting these vessels through distal pancreatectomy (DP), without requiring reconstruction or affecting the likelihood of achieving R0 resection. Thus, even when severe splenic vessel involvement is present, most pancreatic body or tail cancer are classified as R-PC.

However, in pancreatic body or tail cancer, the involvement of these vessels is not surgically significant but is a poor prognostic factor in oncology, along with lymph node metastasis, tumour size, and tumour differentiation [4–6]. Although there have been several studies on splenic vessel involvement [5, 7–9], especially on SpA involvement [10–14], few studies have focused on SpV involvement [15, 16].

Recently, neoadjuvant therapy (NAT) has been widely used in various types of cancers, leading to an improved prognosis. NCCN guidelines recommend the use of NAT for BR-PC and LA-PC [2] to achieve R0 resection. Although the prognostic benefit of NAT for R-PC remains controversial, the Clinical Practice Guidelines for PC of the Japan Pancreas Society, published in 2019, suggest neoadjuvant chemotherapy (NAC) for R-PC based on the results of the randomised prep-02/JSAP-05 trial [17, 18], further demonstrating the importance of NAT.

In this study, we aimed to identify prognostic factors in patients with resectable pancreatic body or tail cancer who underwent DP, examine the significance of SpV involvement both radiologically and pathologically, and discuss the efficacy of NAT.

Patient selection

Between January 2007 and December 2021, 116 consecutive patients underwent DP using radical antegrade modular pancreatosplenectomy (RAMPS) for pancreatic body or tail cancer. Preoperatively, these patients were classified based on the NCCN Clinical Practice Guidelines v.2 2022 [2] into four categories: R (n = 88), BR (n = 11), LA-UR (n = 11), and metastatic unresectable (UR-M, n = 6) (Fig. 1).

This study examined 88 patients with R-PC who did not exhibit PV/SMV involvement or abutment of the CA, CHA, or SMA to elucidate the importance of splenic vessel involvement. Univariate and multivariate analyses were performed to compare clinicopathological characteristics, intraoperative results, and pathological findings in relation to overall survival (OS) and recurrence-free survival (RFS) (Tables 1 and 2 and Fig. 2).

Table 1

Univariate and multivariate analyses to clarify the predictor of overall survival of the 88 patients with resectable pancreatic body or tail cancer who underwent distal pancreatectomy
Variable (n = 88)	Univariate analysis			Multivariate analysis
Variable (n = 88)	HR	95%CI	p-value	HR	95%CI	p-value
Age	1.026	0.986–1.069	0.206
Sex (male/female)	1.104	0.555–2.197	0.779
Body mass index	0.911	0.817–1.017	0.099
Tumour location (body/tail)	0.592	0.268–1.305	0.194
Neoadjuvant therapy	2.068	1.002–4.266	0.049	-	-	-
Pre-operative blood examination
CEA level (ng/mL)	1.016	1.006–1.026	0.002	1.015	1.015–1.004	0.006
CA19-9 level (U/L)	1.000	1.000–1.001	0.467
NLR	0.999	0.835–1.195	0.992
PNI	0.899	0.835–0.976	0.004	-	-	-
Intraoperative findings
Operation time (min)	1.003	1.000–1.006	0.061
Blood loss (ml)	1.000	1.000–1.001	0.159
RAMPS (anterior/posterior)	1.314	0.614–2.811	0.482
Laparoscopic surgery	0.243	0.058–1.015	0.052
Postoperative complication ≥ CD3a	1.388	0.679–2.841	0.369
Pathological findings
Tumour size (mm)	1.030	1.009–1.052	0.009	1.032	1.010–1.055	0.005
Lymph node metastasis	1.220	0.605–2.460	0.578
Anterior serosal invasion	0.955	0.491–1.855	0.891
Retroperitoneal invasion	1.263	0.649–2.457	0.492
Splenic artery invasion	0.688	0.266–1.776	0.439
Splenic vein invasion	2.270	1.106–4.662	0.026	2.684	1.199–6.008	0.016
Perineural invasion	1.403	0.580–3.391	0.452
Non-curative resection	1.968	0.813–4.762	0.133
Non-completion of adjuvant therapy	4.175	2.117–8.237	< 0.001	5.593	2.648–11.814	< 0.001
CEA: carcinoembryonic antigen, CA: cancer antigen, NLR: Neutrophil-to-lymphocyte ratio, PNI: Prognostic Nutritional Index, RAMPS: radical antegrade modular pancreatosplenectomy, CD: Clavien–Dindo, HR: hazard ratio, CI, confidence interval

Table 2

Univariate and multivariate analyses to clarify the predictor of recurrence-free survival of the 88 patients with resectable pancreatic body or tail cancer who underwent distal pancreatectomy
Variable (n = 88)	Univariate analysis			Multivariate analysis
Variable (n = 88)	HR	95%CI	p-value	HR	95%CI	p-value
Age	1.024	0.990–1.059	0.162
Sex (male/female)	0.686	0.369–1.275	0.233
Body mass index	0.909	0.827–1.000	0.050	-	-	-
Tumour location (body/tail)	0.674	0.336–1.353	0.267
Neoadjuvant therapy	1.609	0.894–2.896	0.113
Pre-operative blood examination
CEA level (ng/mL)	1.012	1.003–1.021	0.011	1.013	1.003–1.023	0.009
CA19-9 level (U/L)	1.000	1.000–1.001	0.112
NLR	1.082	0.957–1.223	0.208
PNI	0.944	0.889–1.003	0.062
Intraoperative findings
Operation time (min)	1.002	0.999–1.005	0.116
Blood loss (ml)	1.000	1.000–1.001	0.171
RAMPS (anterior/posterior)	1.268	0.672–2.392	0.463
Laparoscopic surgery	0.504	0.214–1.185	0.116
Postoperative complication ≥ CD3a	1.443	0.793–2.626	0.230
Pathological findings
Tumour size (mm)	1.036	1.018–1.054	< 0.001	1.033	1.014–1.052	< 0.001
Lymph node metastasis	2.036	1.146–3.614	0.015
Anterior serosal invasion	1.353	0.768–2.386	0.295
Retroperitoneal invasion	1.714	0.969–3.033	0.064
Splenic artery invasion	1.216	0.620–2.384	0.569
Splenic vein invasion	3.445	1.910–6.212	< 0.001	3.232	1.736–6.018	< 0.001
Perineural invasion	1.992	1.015–3.909	0.045
Non-curative resection	1.595	0.715–3.556	0.254
Non-completion of adjuvant therapy	2.243	1.252–4.018	0.007	2.516	1.362–4.649	0.003
CEA: carcinoembryonic antigen, CA: cancer antigen, NLR: Neutrophil-to-lymphocyte ratio, PNI: Prognostic Nuritional Index, RAMPS: radical antegrade modular pancreatosplenectomy, CD: Clavien–Dindo, HR: hazard ratio, CI, confidence interval

Clinical and follow-up information of the patients was obtained from a database maintained by the Department of Hepatobiliary Pancreatic and Transplant Surgery at Mie University Hospital.

Radiological evaluation of SpV involvement

The radiographic involvement of the SpV was assessed using multidetector-row computed tomography (MD-CT) by an experienced radiologist blinded to clinical and pathological data. The assessment graded SpV involvement as clear, abutment, or encasement based on previous studies [8, 10]. Abutment was defined as > 180° tumour involvement, and the encasement as > 180° circumferential involvement of the tumour(Fig. 3a, b, c, and d). SpV occlusion was classified as encasement.

The impact of radiological SpV involvement was evaluated by dividing the 88 patients into two groups: those with clear/abutment involvement (n = 45) and those with encasement (n = 43) (Table 3 and Figs. 1 and 3). Patients who underwent NAT were assessed before NAT.

Table 3

Comparisons of clinicopathological characteristics according to radiological splenic vein involvement status
Variables	Clear/abutment (n = 45)	Encasement (n = 43)	p-value
Age	73.5 (44–89)	71.5 (46–87)	0.358
Sex (male/female)	28/17	29/14	0.660
Body mass index	21.4 (18.2–34.7)	21.6 (14.0–28.8)	0.468
Tumour location (body/tail)	8/37	6/37	0.773
Neoadjuvant therapy	17 (37.8%)	35 (81.4%)	< 0.001
Pre-operative blood examination
CEA level (ng/mL)	2.9 (0.9–210.8)	3.1 (1.3–21.1)	0.613
CA19-9 level (U/L)	51.2 (0.1–3039.7)	46.5 (0.1–1153.3)	0.872
NLR	2.00 (0.85–8.84)	2.4 (0.81–13.35)	0.306
PNI	46.7 (37.4–58.2)	45.5 (32.9–56.4)	0.312
Intraoperative findings
Operation time (min)	360 (171–580)	340 (156–697)	0.494
Blood loss (ml)	425 (0–3100)	551 (0–2050)	0.767
RAMPS (anterior/posterior)	17/28	11/32	0.257
Laparoscopic surgery	9 (20.0%)	10 (23.3%)	0.798
Postoperative complication ≥ CD3a	12 (26.7%)	13 (30.2%)	0.814
Pathological findings
Tumour size (mm)	20 (6–70)	30 (1–80)	0.009
Lymph node metastasis	15 (33.3%)	15 (36.6%)	0.823
Anterior serosal invasion	21 (46.7%)	24 (55.8%)	0.404
Retroperitoneal invasion	16 (35.6%)	29 (67.4%)	0.003
Splenic artery invasion	6 (13.3%)	10 (23.3%)	0.276
Splenic vein invasion	4 (8.9%)	17 (39.5%)	< 0.001
Perineural invasion	2 (4.4%)	13 (30.2%)	0.001
Non-curative resection	2 (4.4%)	4 (9.3%)	0.185
Completion of Adjuvant therapy	30 (66.7%)	31 (72.1%)	0.648
CEA: carcinoembryonic antigen, CA: cancer antigen, NLR: Neutrophil-to-lymphocyte ratio, PNI: Prognostic Nuritional Index, RAMPS: radical antegrade modular pancreatosplenectomy, CD: Clavien–Dindo
Data are expressed as number (percentage), median (range).

Neoadjuvant therapy

To improve the prognosis and achieve the R0 resection of patients with pancreatic body or tail cancer, our institution administered neoadjuvant gemcitabine monotherapy (800 mg/m² on days 1, 8, 22, and 29 for one cycle) with radiation (45.0–50.4 Gy) from February 2005 to October 2011. Subsequently, to further improve prognosis, the protocol was changed from gemcitabine alone to include two cycles of gemcitabine (800 mg/m², biweekly) plus S-1 (80 mg/m², 21 days every 4 weeks) therapy, with or without radiation, starting from November 2011. NAT is strongly recommended for patients who (1) have radiographic major vessel involvement, such as of CA/CHA/SMA/SpV or PV/SMV/SpV; (2) have regional lymph node metastasis; or (3) have abnormally high carbohydrate antigen 19 − 9 (CA19-9) levels. Since February 2020, all patients with PC were initially administered adjuvant gemcitabine plus S-1 therapy with or without radiation, according to the clinical practice guidelines for PC 2019 from the Japan Pancreas Society [17]. To assess the significance of NAT, we classified the 88 patients into three groups: those without NAT (n = 36), those with NAC (n = 19), and those who received neoadjuvant chemoradiotherapy (NCRT, n = 33) shown (Table 4and Figs. 1 and 4).

Table 4

Comparisons of clinicopathological characteristics between patients treated with or without neoadjuvant therapy for resectable pancreatic body or tail cancer
Variables	Without NAT (n = 36)	With NAC (n = 19)	With NCRT (n = 33)	p-value
Age	75.5 (44–89)	74.0 (60–83)	69.0 (46–85)	0.024**
Sex (male/female)	23/13	13/6	21/12	0.931
Body mass index	21.4 (15.4–28.3)	24.2 (16.9–34.7)	21.0 (14.0–28.4)	0.031***
Tumour location (body/tail)	6/30	2/17	6/27	0.758
Neoadjuvant therapy
Chemotherapy (GEM/S1/GEM + S1/GnP)	-	0/0/18/1	10/1/22/0
Radiotherapy (45/50.4Gy)	-	-	10/22
Radiological evaluation
Pre-treatment tumour size (mm)	-	25.3 (11.2–37.0)	30.7 (11.5–75.2)	0.007***
Pre-operative tumour size (mm)	22.3 (9.2–52.5)	20.2 (9.0–33.6)	28.4 (9.1–83.8)	< 0.001^, *****
Pre-treatment SpV encasement	-	9 (47.4%)	26 (78.8%)	< 0.001***
Pre-operative SpV encasement	8 (22.2%)	9 (47.4%)	26 (78.8%)	< 0.001^,^,******
Pre-operative blood examination
CEA level (ng/mL)	3.0 (0.9–210.8)	2.7 (1.3–5.4)	3.5 (1.1–16.8)	0.548
CA19-9 level (U/L)	79.1 (0.1–3039.7)	38.3 (0.4–214.1)	39.9 (0.1–688.0)	0.214
NLR	2.03 (0.81–8.84)	2.08 (0.85–6.40)	2.40 (1.03–13.35)	0.492
PNI	46.6 (37.4–58.2)	46.8 (39.9–53.3)	44.9 (32.9–54.7)	0.163
Intraoperative findings
Operation time (min)	356 (156–697)	370 (174–580)	335 (171–650)	0.375
Blood loss (ml)	600 (0–3100)	341 (26–1630)	564 (100–2825)	0.310
RAMPS (anterior/posterior)	19 (52.8%)	12 (63.2%)	29 (87.9%)	0.007**
Laparoscopic surgery	8 (22.2%)	8 (42.1%)	3 (9.1%)	0.020***
Postoperative complication ≥ CD3a	10 (27.8%)	7 (36.8%)	8 (24.2%)	0.621
Pathological findings
Tumour size (mm)	25 (7–55)	20 (6–45)	23 (1–80)	0.606
Lymph node metastasis	14 (38.9%)	8 (42.1%)	8 (25.8%)	0.404
Anterior serosal invasion	20 (55.6%)	9 (47.4%)	16 (48.5%)	0.786
Retroperitoneal invasion	19 (52.8%)	9 (47.4%)	17 (51.5%)	0.928
Splenic artery invasion	6 (16.7%)	5 (26.3%)	5 (15.2%)	0.576
Splenic vein invasion	6 (16.7%)	5 (26.3%)	10 (30.3%)	0.398
Perineural invasion	25 (69.4%)	10 (52.8%)	20 (60.6%)	0.454
Non-curative resection	2 (5.6%)	3 (15.8%)	4 (12.2%)	0.749
Completion of Adjuvant therapy	25 (69.4%)	13 (68.4%)	23 (69.7%)	0.995
NAC: neoadjuvant chemotherapy, NCRT: neoadjuvant chemoradiotherapy, GEM, Gemcitabine, GnP: GEM + nab-Paclitaxel, SpV: splenic vein, CEA: carcinoembryonic antigen, CA: cancer antigen, NLR: Neutrophil-to-lymphocyte ratio, PNI: Prognostic Nuritional Index, RAMPS: radical antegrade modular pancreatosplenectomy, CD: Clavien–Dindo, Data are expressed as number (percentage), median (range)
: without NAT vs. with NAC, : without NAT vs. with NCRT, **: with NAC vs. with NCRT

Surgical procedures for pancreatic body or tail cancer

For pancreatic body or tail cancer, RAMPS, developed by Strasberg et al., was performed according to our previous reports [19, 20].

Pathological evaluation

All specimens were according to the 8th International Union Against Cancer (UICC) guidelines [21].

Adjuvant chemotherapy and follow-up

Patients received adjuvant chemotherapy (AC) 4–6 weeks after surgery, except those with poor performance status or refused it. The AC was gemcitabine from February 2005 to May 2013 and S-1 in June 2013. Patients who completed at least 6 months of AC were considered to have completed AC. After surgery, all patients underwent MD-CT scanning every 4 months during the first 2 years and then every 6 months.

Postoperative complications

Postoperative complications were graded according to the Clavien–Dindo classification [24].

Statistical analysis

Continuous and categorical variables are expressed as median (range) and compared using the Mann-Whitney U and chi-square tests, respectively. Categorical variables were analysed using Fisher’s exact test or the chi-square test, as appropriate. For patients requiring reassessment, the date of initial treatment was selected as the starting point for measuring the survival time. OS and RFS were evaluated using the Kaplan–Meier method and compared between groups using the log-rank test. The final follow-up day was December 31, 2022. Multivariate analysis was performed, and hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated using a stepwise Cox proportional hazards model. Variables with a significance of p < 0.05 in the univariate analysis were used in the multivariate analysis. Comparisons in the univariate analysis were conducted using the chi-square test with Yates correction. The cut-off values for preoperative carcinoembryonic antigen (CEA) levels and tumour size were calculated using a software tool (Cut-off Finder; http://molpath.charite.de/cut-off) [23], and the variables were dichotomised for further survival analyses using the Kaplan–Meier method. All statistical analyses were performed using SPSS version 28 (IBM Corp., Armonk, NY, USA). Statistical significance was set at p < 0.05.

Prognostic factors for OS and RFS of the 88 patients with resectable pancreatic body or tail cancer who underwent DP

The prognostic factors for OS were shown in Table 1. Univariate analysis identified several poor prognostic factors: NAT (p = 0.049), higher pre-operative CEA levels (p = 0.002), lower pre-operative prognostic nutritional index (p = 0.004), larger tumour size (p = 0.005), pathological SpV invasion (p = 0.026), and non-completion of AC (p < 0.001). According to multivariate analysis, higher pre-operative CEA levels (HR 1.015, 95% CI 1.015–1.004, p = 0.006), larger tumour size (HR 1.032, 95% CI 1.010–1.055, p = 0.005), pathological SpV invasion (HR 2.684, 95% CI 1.199–6.008, p < 0.010), and non-completion of AC (HR 5.593, 95% CI 2.648–11.814, p < 0.001) were identified as independent poor prognostic factors.

With regard to the RFS (Table 2). Univariate analysis identified the following poor prognostic factors: lower body mass index (p = 0.05), higher pre-operative CEA levels (p = 0.011), larger tumour size (p < 0.001), pathological SpV invasion (p < 0.001), and non-completion of AC (p = 0.007). Multivariate analysis identified higher pre-operative CEA levels (HR 1.013, 95% CI 1.003–1.023, p = 0.009), larger tumour size (HR 1.033, 95% CI 1.014–1.052, p < 0.001), pathological SpV invasion (HR 3.232, 95% CI 1.736–6.018, p < 0.001), and non-completion of AC (HR 2.516 95% CI 1.362–4.649, p = 0.003) as independent poor prognostic factors.

The optimal cut-off values of pre-operative CEA levels and tumour size were determined using the Cutoff Finder software [23]. The pre-operative CEA levels for OS and RFS of 8.4 and 5.6 ng/mL, and tumour sizes for OS and RFS of 50 and 25 mm, respectively, were identified as the best cut-off values to differentiate patient prognoses. As shown in Fig. 2a and b, patients with pre-operative CEA levels higher than 8.4 ng/mL had a significantly worse OS than those with lower than 8.4 ng/mL (5-year OS: 22.7% vs. 60.5%, p = 0.028). Similarly, patients with pre-operative CEA levels higher than 5.6 ng/mL had a significantly shorter RFS than those with lower than 5.6 ng/mL (5-year RFS, 19.0% vs. 46.3%; p = 0.012).

Regarding tumour size, patients with tumours ≥ 50 mm had a significantly worse OS than those with tumours < 50 mm (5-year OS: 10.0% vs. 60.5%, p < 0.001). Patients with tumours ≥ 25 mm had a significantly shorter RFS than those with tumours < 25 mm (5-year RFS: 20.1% vs. 58.5%, p < 0.001) (Fig. 2c and d).

Furthermore, patients with SpV invasion had significantly worse OS (5-year OS: 41.6% vs. 59.0%, p = 0.022) and RFS (5-year RFS: 10.7% vs. 48.1%, p < 0.001) than those without SpV invasion (Fig. 2e and f).

Patients who completed AC had significantly better OS (5-year OS: 32.9% vs. 65.9%, p < 0.001) and remaining RFS (19.3% vs. 46.6%, p = 0.005) than those who could not complete AC (Fig. 2g and h).

Correlation between radiological and pathological SpV involvement

The correlation between the radiological and pathological SpV involvement is shown in Fig. 3e. Out of 45 patients with radiological SpV clear/abutment, 4 (8.9%) were found to have pathological SpV invasion. In contrast, of the 43 patients who showed radiological SpV encasement, 17 (39.5%) had SpV invasion. The sensitivity and specificity for identifying pathological SpV invasion were 81.0% and 61.2%, respectively.

Comparisons of clinicopathological characteristics according to radiological SpV involvement status

When comparing patients with clear/abutment (n = 45) and encasement (n = 43) regarding radiological SpV involvement before NAT (Table 3), patients with clear/abutment had a significantly lower induction rate of NAT than those with encasement (37.8% vs. 81.4%, p < 0.001). Although the intraoperative findings were comparable between the two groups, patients with encasement had significantly larger tumours (20 vs. 30 mm, p = 0.009). Furthermore, patients with encasement demonstrated significantly higher rates of retroperitoneal invasion (35.6% vs. 67.4%, p = 0.003), SpV invasion (8.9% vs. 39.5%, p < 0.001), and perineural invasion (4.4% vs. 30.2%, p = 0.001) than those with clear/abutment.

Comparison of survival according to radiological SpV involvement status

When comparing the OS and RFS of patients with clear/abutment and encasement in relation to radiological SpV involvement (Fig. 3f and g), patients with encasement had significantly worse OS (5-year OS: 41.0% vs. 68.1%, p = 0.039) and remaining RFS (5-year RFS: 21.5% vs. 55.7%, p < 0.001) than those with SpV clear/abutment.

Comparisons of clinicopathological characteristics between patients treated with or without neoadjuvant therapy for resectable pancreatic body or tail cancer

When comparing patients without NAT (n = 36), with NAC (n = 19), and with NCRT (n = 33) (Table 4), patients who received NCRT were significantly younger than those without NAT (69.0 vs. 75.5 years, p = 0.024), and the body mass index of patients who received NCRT was significantly lower than that of patients who received NAC (21.0 vs. 24.2. p = 0.031).

Regarding the results of radiological evaluations, patients treated with NCRT had significantly larger tumours before treatment than did those treated with NAC (30.7 mm vs. 25.3 mm, p = 0.007). Even after treatment, the tumour size of patients with NCRT (28.4 mm) was still significantly larger than that of those without NAT (22.3 mm) or those with NAC (20.2 mm, both p < 0.001).

The rate of pre-treatment SpV encasement in patients treated with NCRT was significantly higher than that in patients treated with NAC (78.8% vs. 47.4%, p < 0.001). Although the rate of SpV encasement did not change after NAT, without NAT (22.2%), with NAC (47.4%), or with NCRT (78.8%), it was significantly higher in patients who received NAC or NCRT (p < 0.001).

Posterior RAMPS was performed significantly more often in patients who received NCRT than in those without NAT (87.9% vs. 52.8%, p = 0.007). In contrast, laparoscopic surgery was performed significantly more often in patients who received NAC than in those who received NCRT (42.1% vs. 9.1%, p = 0.020).

Comparison of survival between patients treated with or without neoadjuvant therapy for resectable pancreatic body or tail cancer

Comparison of the OS and RFS of patients without NAT (n = 36), with NAC (n = 19), and with NCRT (n = 33) (Table 4), those who received NCRT revealed significantly worse OS (5-year OS: 68.0% vs. 71.6% vs. 36.1%, p = 0.025) and RFS (5-year RFS: 48.6% vs. 59.6% vs. 21.7%, p = 0.045) than those of patients without NAT or with NAC (Fig. 4a and b). When comparing the OS and RFS of the three groups with or without SpV encasement, there were no significant differences among the three groups (Fig. 4c–f).

Several poor prognostic factors have been reported for pancreatic body or tail cancer [4–6]. SpV involvement has been highlighted as a specific factor for pancreatic body or tail cancer. In this study, we first conducted a prognostic factor analysis for the survival of patients with resectable pancreatic body or tail cancer, which account for the majority of DP cases. Higher pre-operative CEA levels, larger tumour size, pathological SpV invasion, and AC non-completion of AC were identified as independent poor prognostic factors for both OS and RFS. Therefore, we examined the importance of radiological SpV involvement and found that patients with radiological SpV encasement had significantly worse OS and RFS. Finally, we examined the possibility of neoadjuvant therapy for resectable pancreatic body or tail cancer. However, neither NAC nor NCRT improved radiological SpV encasement or demonstrated prognostic efficacy.

A negative survival impact of pathological splenic vessel involvement in pancreatic body or tail cancer [9], especially with respect to SpA involvement [5, 10–14], has been reported. In our study, SpV invasion and tumour size, but not SpA invasion, were identified as independent prognostic factors, consistent with previous literature [15, 16]. There are several possible explanations for the discrepancy. First, it may be related to structural differences between the walls of the SpA and SpV. The SpA is surrounded by the nerve plexus and has a thick vessel wall, making it difficult for the tumour to invade beyond the vessel adventitia and into the intima. Alternatively, the SpV wall is thin, allowing easier tumour invasion into blood vessels, facilitating bloodstream spread and liver metastasis. Mizumoto et al. reported a strong association between pathological SpV invasion and early liver metastasis after surgery because of the role of the SpV as a primary drainage vessel from the pancreatic body and tail that leads directly into the PV [16]. Second, there may be a relationship between the directions of blood flow in the SpA and SpV. If tumour cells enter the bloodstream as circulating tumour cells (CTCs) from the SpA, the first entry site is the spleen, which is responsible for tumour immunity [24]. In contrast, if tumour cells enter the bloodstream as CTCs from the SpV, they would flow directly to the liver, the main site of PC metastatic recurrence. Future studies should investigate the mechanisms underlying the pathological involvement of the splenic vessels.

Tumour size is a prognostic factor in various cancers; however, it is considered an oncologically poor prognostic factor in itself. In addition, invasion of the surrounding splenic vessels by larger tumours is also a critical factor. In this study, 18 of 43 patients (41.9%) with tumour sizes ≥ 25 mm, which is the cut-off for RFS, and 3 of 45 patients (6.7%) with tumours < 25 mm had pathological SpV invasion.

Radiological involvement of the SpV can predict the pathological invasion of the same vessels with 81.0% sensitivity and 61.2% specificity. Therefore, it is considered a poor prognostic factor along with pathological SpV involvement. Recently, five studies suggested that radiological splenic vessel involvement can be a negative prognostic indicator. Among these, four studies found that radiological SpA involvement is a significant independent predictor of poor prognosis [7, 8, 10, 11]. Additionally, two studies identified radiological SpV involvement as an independent poor prognostic factor [15, 16]. However, it is difficult to evaluate the significance of radiological SpV involvement without considering its impact. There was a significant overlap between radiological SpV and SpA involvement due to the anatomical proximity of the two major vessels running parallel to each other. In this study, 36 (83.7%) of the 43 cases of radiological SpV involvement were complicated by radiological SpA involvement.

The survival benefits of NAT for R-PC are still debatable [18, 25, 26], although NCCN and Japan guidelines [2, 19] recommend the use of NAT for BR-PC. Two studies using propensity-matched analyses focused on R-PCs located in the pancreatic body and tail [27, 28]. Nassour et al. reported that NAT (n = 353) had a higher adjusted OS than upfront surgery (n = 353). In contrast, Lof et al. reported no improvement in OS with NAT (n = 94) compared with that of upfront surgery (n = 94). However, a sensitivity analysis of 251 patients with radiological splenic vessel involvement indicated that NAT (n = 37) was associated with prolonged OS compared to upfront surgery. In this study, the prognostic impact of NAT could not be observed, regardless of radiological SpV involvement. One reason for this is that patients treated with NAC and NCRT included a significant number of patients with larger tumours or radiological splenic vessel involvement, which are independent poor prognostic factors, when compared with those without NAT. Second, gemcitabine alone or in combination with S1-based NAC and NCRT used in this study may not have been sufficiently effective in reducing tumour size and improving tumour splenic vessel involvement. Therefore, there is an urgent need to develop more potent and optimal regimens and appropriate dosing periods for NAT. In addition, we believe that pre-operative CA19-9 and CEA levels can be helpful in determining the efficacy of treatment after NAT.

This study has some limitations. First, this was a retrospective cohort study performed at a single institution; therefore, the results need to be confirmed in prospective clinical trials. Second, there were several changes in the indications, regimens, and schedules of NAC and AC during the study period. Third, as over 80% of patients had radiological involvement of both SpA and SpV, it was difficult to determine which splenic vessels contributed the most to the prognosis.

Radiological and pathological SpV involvement in patients with resectable pancreatic body or tail cancer was strongly associated with early recurrence and poor long-term survival, regardless of NAT. New treatment strategies, including NAT and AC, should be developed for patients with SpV involvement.

Statements and Declarations

Funding information: This study received no funding.

Conflict of Interest: Authors declare no conflict of interests for this article.

Data accessibility statement: The data analysed during the current study are available from the corresponding author on reasonable request.

Ethics approval: The protocol for this research project has been approved by a suitably constituted Ethics Committee of the institution and it conforms to the provisions of the Declaration of Helsinki. Committee of the Mie University of Japan, Approval No. H2021-024.

Consent to participate: All participants provided informed consent for participation and for the use of their medical records through an opt-out form.

Authors’ contributions

Study conception and design: Naohisa Kuriyama, Masashi Kishiwada, and Shugo Mizuno

Acquisition of data: Naohisa Kuriyama, Tatsuya Sakamoto, Yu Fujimura, Takuya Yuge, Daisuke Noguchi, Takahiro Ito, Aoi Hayasaki, Takehiro Fujii, Yusuke Iizawa, Yasuhiro Murata, Akihiro Tanemura, Miki Usui, and Motonori Nagata

Analysis and interpretation of data: All the authors participated in the critical revision of the manuscript for important intellectual content. All the authors approved the final version to be published and agreed to be accountable for all aspects of the work, ensuring that questions related to the accuracy or integrity of any part of the work were appropriately investigated and resolved.

Drafting of manuscript and critical revision of manuscript: Naohisa Kuriyama, Shugo Mizuno

All authors have read and approved the manuscript.

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Impact of Radiological and Pathological Splenic Vein Involvement in Patients with Resectable Pancreatic Body or Tail Cancer

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Abstract

Purpose

Methods

Results

Conclusion

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Introduction

Methods

Patient selection

Radiological evaluation of SpV involvement

Neoadjuvant therapy

Surgical procedures for pancreatic body or tail cancer

Pathological evaluation

Adjuvant chemotherapy and follow-up

Postoperative complications

Statistical analysis

Results

Correlation between radiological and pathological SpV involvement

Comparisons of clinicopathological characteristics according to radiological SpV involvement status

Comparison of survival according to radiological SpV involvement status

Discussion

Conclusion

Declarations

References

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