Prognostic impact of histopathological features and serum inflammatory markers in patients with gastric cancer undergoing neoadjuvant therapy

Abstract

BACKGROUND

Neoadjuvant therapies induce tumor regression, resulting in improved surgical resection and pathologic complete response rates, as well as long-term disease-free and overall survival (OS). In addition to the tumor regression score, serum inflammatory markers, including neutrophil, lymphocyte, platelet, and serum albumin levels, are used to determine prognosis.

AIM

To investigate the effect of histological features and serum inflammatory markers on the prognosis of gastric cancer following neoadjuvant treatment.

METHODS

Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and serum albumin levels were retrospectively recorded for 177 patients receiving neoadjuvant 5-fluorouracil, leucovorin, oxaliplatin and docetaxel chemotherapy. Disease-free and OS were analyzed based on tumor histopathological features, type of surgery, regression scores, and serum inflammatory markers.

RESULTS

Patients over 65 years of age, those with lymphovascular or perineural invasion, hypoalbuminemia, and those who did not receive adjuvant therapy were found to be at higher risk for shorter recurrence/relapse intervals [hazard ratio (HR): 1.64, P = 0.04; HR: 4.20, P < 0.001; HR: 1.87, P = 0.03; HR: 3.5, P < 0.001; and HR: 2.73, P = 0.01, respectively]. Lymphovascular invasion, R1 resection, lack of adjuvant treatment, and hypoalbuminemia negatively influenced OS (HR: 3.68, P < 0.003; HR: 2.37, P = 0.01; HR: 3.99, P < 0.001; and HR: 2.50, P = 0.01, respectively). No effect of NLR and PLR was observed.

CONCLUSION

Current neoadjuvant therapies prolong disease-free and OS. The practical application of serum inflammatory markers (NLR and PLR) is limited due to the lack of standard cut-off values. Nutritional status, hypoalbuminemia, and incomplete perioperative chemotherapy have been associated with poor prognosis.

Key Words: Gastric cancer; Neoadjuvant therapy; Neutrophil/lymphocyte ratio; Albumin; Survival

Core Tip: Serum inflammatory markers and nutritional status influence surgical mortality. Perioperative chemotherapy contributes to survival by improving pathological response and prognosis. In addition to the tumor regression score, serum inflammatory markers, such as neutrophil, lymphocyte, platelet levels, and serum albumin levels, are used to determine prognosis. As there are no specific cut-off values for inflammatory markers reported in literature, we investigated the effect of serum levels of these markers and histopathological features on tumor prognosis.

INTRODUCTION

The MAGIC study, which investigated locally advanced gastric and gastroesophageal cancers, demonstrated the benefit of perioperative chemotherapy in improving 5-year survival[1]. Given the hematologic toxicity and tolerability challenges associated with standard docetaxel, cisplatin, and 5-fluorouracil (5-FU) regimens, a modified 14-day docetaxel regimen was proposed. A chemotherapy regimen consisting of 5-FU, leucovorin, oxaliplatin and docetaxel (FLOT) is considered more tolerable than anthracycline-based (epirubicin, cisplatin, 5-FU and/or capecitabine) triple therapy[2,3]. Moreover, FLOT has demonstrated a superior complete response rate compared with epirubicin, cisplatin plus fluorouracil or capecitabine (ECF/ECX, 15% vs 6%, P = 0.02)[4]. FLOT has also shown significantly higher progression-free survival and overall survival (OS) rates relative to ECF/ECX (38% vs 24%, respectively)[4,5]. Adequate nutritional status, indicated by a high serum albumin level and high lymphocyte count, has been linked to a reduction in postoperative complications among patients with gastric cancer. Furthermore, the preoperative neutrophil-to-lymphocyte ratio (NLR) and platelet-to- lymphocyte ratio (PLR) have been identified as prognostic indicators of the neoadjuvant tumor response and OS[6-8]. This study aimed to investigate the relationships of neoadjuvant FLOT chemotherapy with histopathological parameters, serum inflammatory markers and albumin levels, all of which may influence pathologic response evaluation and survival in patients with locally advanced gastric cancer. The primary objective was to assess prognosis by analyzing NLR, PLR, and albumin levels before chemotherapy and surgery.

MATERIALS AND METHODS

This retrospective analysis included 177 patients diagnosed with locally advanced gastric cancer who received neoadjuvant FLOT chemotherapy from September 2017 to December 2024. Endoscopic biopsy and staging with computed tomography (CT) and positron emission tomography/CT (PET-CT) scans were performed for all patients. After four cycles of neoadjuvant FLOT chemotherapy, laparoscopic surgery was conducted. Pathologic staging was performed according to the tumor-node-metastasis classification[9]. Serum samples were collected between 1 and 30 days prior to chemotherapy. The following tumor marker values were recorded; hemoglobin level, neutrophil count, platelet count, lymphocyte count, albumin level, and carcinoembryonic antigen level. The median values of NLR and PLR were also determined. Neoadjuvant chemotherapy consisted of four cycles of oxaliplatin (85 mgr/m²), docetaxel (50 mgr/m²), leucovorin (200 mgr/m²), and 5-FU (2600 mgr/m²) administered as a 24-hour infusion every 14 days. Upon completion of this regimen, response evaluation was conducted using the RECIST 1.1 criteria based on preoperative CT, magnetic resonance imaging or PET/CT[10]. Tumor response was classified as complete remission, partial response, stable disease, or progressive disease. Disease-free survival (DFS) was defined as the time from diagnosis until recurrence, relapse, or death.

Patients who met the following criteria were included: (1) Histopathologically confirmed resectable or potentially resectable (inoperable without comorbidities) gastric cancer; (2) Siewert type 2/or 3 adenocarcinoma; (3) CT1-T4 and/or N0-N+ disease, as determined by CT and/or PET/CT; and (4) Eastern Cooperative Oncology Group[11] physical status of 1or 2, indicating eligibility for FLOT treatment. Patients were excluded if they met any of the following criteria: (1) History of chemotherapy or radiotherapy; (2) Preoperatively detected infection or other blood disorders; (3) Metastatic disease at initial diagnosis; (4) Autoimmune disease or ongoing steroid therapy; (5) Liver or chronic kidney disease; and (6) Missing data.

RESULTS

Patient characteristics are summarized in Table 1. The mean age of 177 patients was 63 years (range: 33-80 years). In total, 125 (70.6%) patients were men and 52 (29.4%) were women. Regarding clinical stage distribution, 130 (73.4%) patients had locally advanced disease, and 47 (26.6%) patients had early-stage disease. Histopathological analysis identified adenocarcinoma in 141 (79.7%) patients and signet-ring cell carcinoma in 36 (20.3%) patients. Poorly differentiated tumors were observed in 90 (50.8%) cases. Among the 177 patients who received neoadjuvant chemotherapy, 150 (84.7%) also received adjuvant chemotherapy. Additionally, 113 (75.3%) patients completed four or five cycles, whereas 37 (24.6%) underwent fewer than four cycles.

Table 1 Characteristics of patient, n (%).

Characteristics	Patients (n = 177)
Age, median	63 (33-80)
Gender
Male	125 (70.6)
Female	52 (29.4)
ECOG
0	107 (60.5)
1	70 (39.5)
Body mass index
< 25	85 (48.0)
≥ 25	89 (50.3)
Unknown	3 (1.7)
Location
Cardia	93 (52.5)
Corpus	52 (29.4)
Antrum	32 (18.1)
Histological type
Adeno	141 (79.7)
Signet-ring cell	36 (20.3)
c-T stage
1-2	29 (16.4)
3-4	148 (83.6)
c-stage
1-2	47 (26.6)
3	130 (73.4)
c-N stage
N0	24 (13.6)
N+	153 (86.4)
Grade
1-2	87 (49.2)
3	90 (50.8)
Neoadjuvant FLOT	177 (100)
Interval between surgery and last chemotherapy, days	43.3 (10-158)
Radiological response
CR	12 (6.8)
PR	91 (51.4)
SD	71 (40.1)
PD	3 (1.7)
CEA (ng/L)
> 5 ng/L	45 (25.4)
< 5 ng/L	113 (63.8)
Missing	19 (10.7)
HER-2 status
Negative	158 (89.3)
Positive	9 (5.1)
Missing	10 (5.6)
MSI
Low	142 (80.2)
High	13 (7.3)
Missing	22 (12.4)
Surgery
Total gastrectomy	145 (81.9)
Distal	27 (15.3)
Proximal	5 (2.8)
Surgery
R0	157 (88.7)
R1	20 (11.3)
p-T stage
0-2	64 (36.2)
3-4	113 (63.8)
p-N stage
N0-1	100 (56.5)
N2-3	77 (43.5)
yp stage
0	22 (12.4)
1	29 (16.4)
2	44 (24.9)
3	82 (46.3)
Total lymph node
Positive	115 (64.3)
Negative	64 (35.7)
Lymphovascular invasion
Yes	107 (60.5)
No	70 (39.5)
Perineural invasion
Yes	87 (49.2)
No	90 (50.8)
Pathological response score
CR /near CR (1)	42 (23.7)
PR (2)	76 (42.9)
Poor/unresponsive (3)	59 (33.3)
Adjuvant
Yes	150 (84.7)
No	27 (15.3)
Chemotherapy regimen (n = 150)
FLOT, median 4 (4-8)	122 (81.3)
FOLFOX	16 (10.7)
FOLFIRI	3 (2.0)
FUFA	9 (6.0)
Post operative radiotherapy
Yes	62 (35.0)
No	115 (65.0)
Relapse
No	102 (57.6)
Yes	75 (42.4)
Dead	59 (33.3)
Alive	118 (66.7)
Hb mean g/dL (anemia)
Yes	106 (59.9)
No	71 (40.1)
NLR, median	2.06 (0.76-30.0)
Low	84 (47.5)
High	91 (51.4)
PLR, median	128.4 (43.9-572)
Low	87 (49.1)
High	88 (49.7)

ECOG: Eastern Cooperative Oncology Group; FLOT: 5-fluorouracil, leucovorin, oxaliplatin and docetaxel chemotherapy; c-T: Clinic tumor stage; c-N: Clinic lymph node stage; CR: Complete response; PR: Partial response; SD: Stable disease; PD: Progressive disease; MSI: Microsatellite instability; pT: Pathological tumor stage; pN: Pathological node stage; yp stage: Post neoadjuvant therapy stage; NLR: Neutrophil-to-lymphocyte count; PLR: Platelet-to-lymphocyte count; CEA: Carcinoembryonic antigen.

Patients underwent total gastrectomy or proximal and/or distal subtotal gastrectomy, proximal and distal surgical margins were reported. Pathological response was assessed using the Becker scoring system; with grade 1 assigned for no tumor or < 10% residual tumor, grade 2 for 10%-50% residual tumor within the tumor area, and grade 3 for > 50% residual tumor[12]. Patients with a grade 1 response were classified as- responders, whereas those with grades 2 and 3 responses were regarded as-non-responders[13]. In R0 resection, both microscopic and macroscopic margins were negative, in R1 resection, the macroscopic tumor was removed, but the surgical margin remained microscopically positive (Table 1). The mean interval between the final chemotherapy treatment and surgical intervention was 43.3 days (range: 10-158 days). Of the patients, 145 (81.9%) underwent total gastrectomy, 27 (15.3%) underwent distal subtotal gastrectomy, and five (2.8%) underwent proximal gastrectomy. D2 lymph node dissection was performed laparoscopically in all patients. R0 resection was achieved in 157 (88.7%) patients, whereas 20 (11.3%) patients underwent R1 resection.

The distribution according to post neoadjuvant therapy (yp) stage was as follows: Stage 0 in 22 (12.4%) patients, stage 1 in 29 (16.4%) patients, stage 2 in 44 (24.9%) patients, and stage 3 in 82 (46.3%) patients. Tumor regression scoring (RS) was classified as: RS1 (complete or near complete response) in 42 (23.7%), RS2 (partial response) in 76 (42.9%) patients, and RS3 (> 50% residual tumor) in 59 (33.3%) patients. In the univariate analysis, preoperative and histopathologic variables were evaluated for potential associations with DFS. Sex, Eastern Cooperative Oncology Group physical status, HER-2 status, microsatellite instability, radiotherapy, NLR, PLR, and anemia were not associated with DFS (Table 2). The median DFS was 18 months in patients with a body mass index (BMI) of < 25 kg/m², it was not reached in those with a BMI of ≥ 25 kg/m². Additionally, the following factors were associated with significantly worse DFS: (1) CT-stage 3-4 compared with stage 1-2, (2) C-N+ and c-N2-3 compared with N0, c-stage 2-3 compared with stage 1; (3) Grade 3 compared with grades 1-2, perineural and lymphovascular invasion compared with no invasion; (4) R1 resection compared with R0 resection; and (5) RS of 2-3 compared with RS1. However, multivariate analysis identified age ≥ 65 years, lymphovascular and perineural invasion, lack of adjuvant therapy, and hypoalbuminemia as poor prognostic factors for a shorter time to relapse [hazard ratio (HR): 1.64, 95% confidence interval (CI): 1.0-2.6, P = 0.04; HR: 4.20, 95%CI: 2.0-8.8, P < 0.001; HR: 1.87, 95%CI: 1.0-3.3, P = 0.03; HR: 3.58, 95%CI: 2.0-6.4, P < 0.001; HR: 2.73, 95%CI: 1.2-5.8, P = 0.01, respectively] (Table 2, Figure 1A-C).

Figure 1 The survival rate of groups of patients. A: Disease-free survival graph in patients with albumin levels < 3.5 vs ≥ 3.5 g/dL; B: Overall survival graph in patients with albumin levels < 3.5 vs ≥ 3.5 g/dL; C: Disease-free survival graph in patients with and without adjuvant chemotherapy; D: Overall survival graph in patients with and without adjuvant chemotherapy.

Table 2 Univariate analysis of disease-free survival by patient and tumor characteristics, n (%).

Population characteristics	Relapse (n = 75)	No relapse (n = 102)	P value	Univariate analysis of DFS, months	P value	Multivariate analysis P value
Age, years			0.41		0.080	HR: 1.64, P = 0.04, CI: 1.019-2.652
< 65	38 (50.7)	58 (56.9)		27.9
≥ 65	37 (49.3)	44 (43.1)		18.5
Gender			0.32		0.110
Male	50 (66.7)	75 (73.5)		33.4
Female	25 (33.3)	27 (26.5)		19.0
ECOG PS			0.04		0.070
0	39 (52.0)	68 (66.7)		33.4
1	36 (48.0)	34 (33.3)		19.9
Body mass index			< 0.001		< 0.001
≥ 25	25 (33.3)	64 (64.6)		NA
< 25	50 (66.7)	35 (35.4)		18.5
Histological type			< 0.001		< 0.001
Adeno	49 (65.3)	92 (90.2)		37.3
Signet ring cell	26 (34.7)	10 (9.8)		15.9
c-T stage			< 0.001		< 0.001
1-2	2 (2.7)	27 (26.5)		NA
3-4	73 (97.3)	75 (73.5)		20.9
c-N stage			0.006		0.011
Negative	4 (5.3)	20 (19.6)		NA
Positive	71 (94.7)	82 (80.4)		22.7
c-stage			< 0.001		< 0.001
1-2	6 (8.0)	41 (40.2)		NA
3	69 (92.0)	61 (59.8)		18.8
Grade			< 0.001		< 0.001
I-II	24 (32.0)	63 (61.8)		NA
III	51 (68.0)	39 (38.2)		17.7
HER-2 status			0.50		0.330
Negative	67 (93.1)	91 (95.8)		27.0
Positive	5 (6.9)	4 (4.2)		15.4
MSI			0.44		0.660
Low	59 (93.7)	83 (90.2)		24.0
High	4 (6.3)	9 (9.8)		20.9
pT stage			< 0.001		< 0.001
0-2	11 (14.7)	53 (52.0)		NA
3-4	64 (85.3)	49 (48.0)		18.8
pN stage			< 0.001		< 0.001
N0-1	21 (28.0)	79 (77.5)		NA
N2-3	54 (72.0)	23 (22.5)		14.0
yp stage			< 0.001		< 0.001
0-1	6 (8.0)	45 (44.1)		NA
2-3	69 (92.0)	57 (55.9)		18.8
Lymphovascular invasion						HR: 4.20, P < 0.001, CI: 2.000-8.860
No	10 (13.3)	60 (58.8)	< 0.001	NA	< 0.001
Yes	65 (86.7)	42 (41.2)		16.6
Perineural invasion			< 0.001		< 0.001	HR: 1.87, P = 0.03, CI: 1.043-3.374
No	19 (25.3)	71 (69.6)		NA
Yes	56 (74.7)	31 (30.4)		16.7
Surgery			< 000.1		< 0.001
R0	59 (78.7)	98 (96.1)		33.4
R1	16 (21.3)	4 (3.9)		13.0
Becker regression score			< 0.001		< 0.001
1	6 (8.0)	36 (35.3)		NA
2-3	69 (92.0)	66 (64.7)		20.9
Adjuvant therapy			0.001		< 0.001	HR: 3.58, P < 0.001, CI: 2.004-6.409
Yes	56 (74.7)	94 (92.2)		36.0
No	19 (25.3)	8 (7.8)		8.3
Post operative radiotherapy			0.014		0.120
No	41 (54.7)	74 (72.5)		44.9
Yes	34 (45.3)	28 (27.5)		19.0
NLR (median = 2.06)			0.350		0.300
Low	32 (43.8)	52 (51.0)		26.9
High	41 (56.2)	50 (49.0)		27.0
PLR (median = 128.4)			0.310		0.240
Low	33 (45.2)	54 (52.9)		36.0
High	40 (54.8)	48 (47.1)		27.0
Anemia, Hb < 12 g/dL			0.360		0.500
No	33 (44.0)	38 (37.3)		24.0
Yes	42 (56.0)	64 (62.7)		33.4
Albumin, 3.5 g/L			0.016		0.014	HR: 2.73, P = 0.01, CI: 1.278-5.858
High	64 (87.7)	98 (97.0)		27.9
Low	9 (12.3)	3 (3.0)		12.5
CEA			0.69		0.51
< 5 ngr/L	49 (73.1)	64 (70.3)		26.9
> 5 ngr/L	18 (26.9)	27 (29.7)		33.4

DFS: Disease-free survival; HR: Hazard ratio; CI: Confidence interval; ECOG PS: Eastern Cooperative Oncology Group performance status; c-T: Clinic tumor stage; c-N: Clinic lymph node stage; MSI: Microsatellite instability; pT: Pathological tumor stage; pN: Pathological node stage; yp stage: Post neoadjuvant therapy stage; NLR: Neutrophil-to-lymphocyte count; PLR: Platelet-to-lymphocyte count; CEA: Carcinoembryonic antigen; NA: Not available.

The analysis revealed that adjuvant radiotherapy did not have a significant effect on prognosis (P = 0.12). Patients who did not receive adjuvant therapy had a 3.58-fold shorter survival than those who received adjuvant therapy (8.3 vs 36 months, 95%CI: 2.0-6.4, P < 0.001) (Table 2). Additionally, lymphovascular invasion, R1 resection, absence of adjuvant treatment, and hypoalbuminemia were all associated with a negative impact on OS. The HRs and 95%CIs for these factors were as follows: Lymphovascular invasion (HR: 3.68, 95%CI: 1. 53-8.82, P < 0.003), R1 resection (HR: 2.37, 95%CI: 1.21-4.63, P = 0.01), no adjuvant therapy (HR: 3.99, 95%CI: 2.25-7.09, P < 0.001), and hypoalbuminemia (HR: 2.50, 95%CI: 1.19-5.21, P = 0.01) (Table 3, Figure 1B-D). All 177 patients received neoadjuvant FLOT chemotherapy. Among them, 122 (81.3%) received FLOT, 16 (10.7%) received FOLFOX, three (2%) received FOLFIRI, and nine (6%) received adjuvant treatment in the postoperative period. The therapeutic efficacy was as follows: 42 (23.7%) patients achieved a pathologic complete response, 76 (42.9%) patients had a partial response, and 59 (33.3%) patients were non-responders.

Table 3 Multivariate analysis of overall survival by patient and tumor characteristics, n (%).

Population characteristics	Alive, 118 (66.7)	Dead, 59 (33.3)	P value	Univariate analysis of OS, months	P value	Multivariate analysis, P value
Age, years			0.33		0.14
< 65	67 (56.8)	29 (49.2)		NA
≥ 65	51 (43.2)	27 (50.8)		33.6
Gender			0.35		0.12
Male	86 (72.9)	39 (66.1)		26.9
Female	32 (27.1)	20 (33.9)		45.9
ECOG PS			0.06		0.21
0	77 (65.3)	30 (50.8)		NA
1	41 (34.7)	29 (49.2)		29.0
Body mass index			0.003		0.04
≥ 25	68 (59.1)	21 (35.6)		NA
< 25	47 (40.9)	38 (64.4)		27.6
Histological type			< 0.001		< 0.001
Adeno	104 (88.1)	37 (62.7)		45.9
Signet ring cell	14 (11.9)	22 (37.3)		21.5
c-T stage			< 0001		0.001
1-2	28 (23.7)	1 (1.7)		NA
3-4	90 (76.3)	58 (98.3)		28.7
c-N stage			0.06		0.07
Negative	20 (16.9)	4 (6.8)		NA
Positive	98 (83.1)	55 (93.2)		33.4
c-stage			< 0.001		< 0.001
1-2	42 (35.6)	5 (8.5)		NA
3	76 (64.4)	54 (91.5)		27.6
Grade			0.001		< 0.001
I-II	68 (57.6)	19 (32.2)		NA
III	50 (42.4)	40 (67.8)		23.6
HER-2 status			0.990		0.850
Negative	105 (94.6)	53 (94.6)		36.0
Positive	6 (5.4)	3 (5.4)		15.7
MSI			0.34		0.340
Low	96 (89.7)	46 (95.8)		37.3
High	11 (10.3)	2 (4.2)		NA
pT stage			< 0.001		< 0.001
0-2	55 (46.6)	9 (15.3)		NA
3-4	63 (53.4)	50 (84.7)		26.9
pN stage			< 0.001		0.001
N0-1	84 (71.2)	16 (27.1)		NA
N2-3	34 (28.8)	43 (72.9)		21.5
yp stage			< 0.001		< 0.001
0-1	47 (39.8)	4 (6.8)		NA
2-3	71 (60.2)	55 (93.2)		26.9
Lymphovascular invasion			< 0.001		< 0.001	HR: 3.68, P < 0.003, CI: 1.536-8.829
No	63 (53.4)	7 (11.9)		NA
Yes	55 (46.6)	52 (88.1)		26.3
Perineural invasion			< 0.001		< 0.001
No	74 (62.7)	16 (27.1)		NA
Yes	44 (37.3)	43 (72.9)		26.3
Surgery			< 0.001		< 0.001	HR: 2.37, P = 0.01, CI: 1.219-4.634
R0	112 (94.9)	45 (76.3)		37.3
R1	6 (5.1)	14 (23.7)		14.8
Regression score			< 0.001		0.001
1	38 (32.2)	4 (6.8)		NA
2-3	80 (67.8)	55 (93.2)		27.6
Adjuvant			< 0.001		< 0.001	HR: 3.99, P < 0.001, CI: 2.253-7.097
Yes	110 (93.2)	40 (67.8)		NA
No	8 (6.8)	19 (32.2)		11.0
Postoperative radiotherapy			0.03		0.14
No	35 (29.7)	27 (45.8)		NA
Yes	83 (70.3)	32 (54.2)		26.3
NLR (median = 2.06)			0.27		0.33
Low	60 (50.8)	24 (42.1)		37.3
High	58 (49.2)	33 (57.9)		33.4
PLR (median = 128.4)			0.04		0.05
Low	65 (55.1)	22 (38.6)		NA
High	53 (44.9)	35 (61.4)		29.0
Anemia, < 12 g/dL			0.44		0.35
No	45 (38.1)	26 (44.1)		27.2
Yes	73 (61.9)	33 (55.9)		36.0
Albumin, 3.5 g/dL			0.001		0.01	HR: 2.50, P = 0.01, CI: 1.198-5.215
High	114 (97.4)	48 (84.2)		45.9
Low	3 (2.6)	9 (15.8)		15.9
CEA			0.85		0.94
< 5 ngr/L	77 (72.0)	36 (70.6)		36.0
> 5 ngr/L	30 (28.0)	15 (29.4)		37.3

OS: Overall survival; HR: Hazard ratio; CI: Confidence interval; ECOG PS: Eastern Cooperative Oncology Group performance status; c-T: Clinic tumor stage; c-N: Clinic lymph node stage; MSI: Microsatellite instability; pT: Pathological tumor stage; pN: Pathological node stage; yp stage: Post neoadjuvant therapy stage; NLR: Neutrophil-to-lymphocyte count; PLR: Platelet-to-lymphocyte count; CEA: Carcinoembryonic antigen; NA: Not available.

DISCUSSION

The primary objectives of neoadjuvant therapy are to enhance tumor regression, eradicate micro metastases, and ultimately, prolong DFS and OS[14]. The combination of perioperative and postoperative chemotherapy in locally advanced gastric cancer achieves high response rates and extends both DFS and OS. Studies have revealed high complete response-rates (13%-17%) and R0 resection rates exceeding 90%[5,15]. In the MAGIC study, patients who received ECX/ECF chemotherapy in the perioperative period demonstrated better survival outcomes than those who underwent surgery alone, with a median survival of 25 months)[1]. In the FLOT4 phase 2/3 study, 90% of patients who received FLOT chemotherapy in the neoadjuvant period completed treatment; this rate was 46% (162 patients) among patients who received FLOT chemotherapy in the postoperative period[4]. In our study, all patients completed neoadjuvant treatment, and 96 (64%) of the 150 patients who received adjuvant treatment completed four cycles of FLOT chemotherapy. DFS was 3.5-fold shorter (HR: 3.5, 95%CI: 2.0-6.4, P < 0.001), and OS was 3.9-fold shorter (HR: 3.7, 95%CI: 2.2-7.0, P < 0.001) in patients who did not receive adjuvant chemotherapy compared with those who did (Figure 1B-D). In the MAGIC study, 5-year survival rates were 36% in the chemotherapy plus surgery group and 23% in the surgery-only group[1].

In our study, radiotherapy was administered to 62 (35%) patients with a poor response and/or no response (score 3) or R1 resection after neoadjuvant chemotherapy. D2 dissection was performed in all patients. According to the literature, DFS and OS were superior in patients who received postoperative concomitant chemoradiotherapy[16]. The time from the completion of four cycles of neoadjuvant chemotherapy to surgery in our study was 43.3 days. In the FLOT4 phase 2/3 study, the interval from the start of chemotherapy to surgery was 11 weeks[4]. In our cohort, 42 (23.7%) patients exhibited complete or near-complete responses, 76 (42.9%) patents demonstrated partial responses, and 59 (33.3%) patients showed no response (Table 1). In a previous study regarding FLOT, the response rates were 25% for ypT1 and 49% for ypN0 disease. The R0 resection rate was 88.7% (n = 157) in our study, compared with 85.0% (n = 301) in a previous report[4]. According to the MAGIC study, median OS intervals were 25 months with perioperative ECF[1], 35 months with ECX/ECF, 50 months with FLOT[4], and 33.6 months in the present study. The mean follow-up time was 16 months. The comparatively lower OS observed in our study may be attributable to several factors, including a poor regression score in 135 (76.2%) patients, lack of adjuvant chemotherapy in 27 (15.3%) patients, absence of postoperative FLOT treatment in 28 (18%) patients, and a prolonged waiting period before surgery. Patients who underwent surgery after 6 weeks did not show a difference in DFS; however, a significant difference in OS was observed[17]. The absence of a standardized waiting period for surgery has been noted, but patients who underwent surgery within 23-35 days exhibited superior OS and pathologic complete response rates[18]. Relapse occurred in 75 (42.4%) patients and 59 (33.3%) died of disease progression or were lost to follow-up. According to the literature, 64% of patients receiving ECX/ECF and 54% of those receiving FLOT experienced progression, relapse, or death during follow-up[4]. The DFS among our patients was 26.9 months, compared with 18 months in the ECX/ECF arm and 30 months in the FLOT arm according to a previous report[4].

Furthermore, our analysis revealed that DFS intervals were shorter in patients aged ≥ 65 years (HR: 1.64, 95%CI: 1.0-2.6, P = 0.04) , those with lymphovascular invasion (HR: 4.2, 95%CI: 2.0-8.8, P < 0.001), those with perineural invasion (HR: 1.8, 95%CI: 1.0-3.3, P = 0.03), those who did not receive adjuvant therapy (HR: 3.58, 95%CI: 2.0-6.4, P < 0.001), and those with hypoalbuminemia (HR: 2.7, 95%CI: 1.2-5.8, P = 0.01) (Table 2, Figure 1A-C). OS probability was significantly lower in patients with advanced grade cancer (HR: 1.29, 95%CI: 0.66-2.54, P = 0. 44), lymphovascular invasion (HR: 3.68, 95%CI: 1.53-8.82, P < 0.003), R1 resection (HR: 2.37, 95%CI: 1.21-4.63, P = 0.01), absence of adjuvant therapy (HR: 3.99, 95%CI: 2.25-7.0, P < 0.001), and preoperative hypoalbuminemia (HR: 2.50, 95%CI: 1.19-5.21, P = 0.01) (Table 3, Figure 1B-D). Low NLR and PLR levels have been associated with a superior immune inflammatory response and a more favorable tumor regression score, indicating a better prognosis relative to high levels[6]. Studies frequently reveal cut off values of ≥ 160-180 for the NLR and PLR[19]. However, in our study, the median low/high values of the NLR and PLR did not contribute to DFS or OS.

Additionally, the tumor microenvironment and vascular endothelial factors influence the response to neoadjuvant chemotherapy. Immune cells and factors (e.g., CD4⁺ and CD8⁺ cells, monocytes, mast cells, interleukins, fibroblast, and macrophages), along with oxidative stress and genetic alterations in the tumor, play a role in prognosis and treatment response[20]. According to univariate analysis, a high RS was statistically significant; however, it did not remain significant based on multivariate analysis (P = 0.44 and P = 0.48, respectively) (Tables 2 and 3). The finding was attributed to the low number of patients with good response scores (Tables 2 and 3). The literature indicates that patients with an NLR of < 2.38 and PLR of < 188 exhibit superior response scores relative to those with elevated ratios (P = 0.01 and P = 0.05, respectively)[6]. Furthermore, study by Yang et al[21] showed that patients with an NLR of < 2.46 and PLR of < 118 demonstrated higher complete response rates than those with higher ratios. However, the present study did not reveal an association between inflammatory markers (NLR and PLR) and prognosis. DFS and OS were not significantly different between low and high NLR and PLR values (P = 0.30, P = 0.33; P = 0.24, and P = 0.05, respectively). Although a low PLR (< 128.4) was statistically significant, further investigation is needed to determine its clinical significance (P = 0.73) (Table 3). In the literature, low pretreatment PLRs have been associated with better OS relative to high PLRs (33 vs 15 months, P = 0.009), whereas low NLRs have not demonstrated a significant effect on OS (P = 0.231)[22,23].

Anemia and hypoalbuminemia serve as indicators of poor nutrition and chronic inflammation. Chronic inflammation reduces erythrocyte lifespan and decreases albumin production in the liver. Additionally, tumor cells binding to plasma albumin facilitate cancer progression[24]. Low albumin and hemoglobin levels exert an immunosuppressive effect by impairing DNA repair mechanisms through oxidation[21,24]. Hypoalbuminemia induces oxidative stress and leads to a poor prognosis, independent of factors such as cancer stage, nutritional status, type of surgery, or metastatic status[24]. In the present study, hemoglobin levels (< 12 g/dL in women and < 13 g/dL in men) were not significant for DFS or OS (P = 0.50 and P = 0.35, respectively). However, DFS and OS were shorter in patients with albumin levels of < 3.5 g/L. Patients with albumin levels of ≥ 3.5 g/L had DFS and OS intervals of 27.9 months and 45.9 months, respectively, compared with 12.5 months and 15.9 months among individuals with levels of < 3.5 g/L (P = 0.01) (Table 2). According to multivariate analysis, low albumin levels were associated with a 2.5-fold decrease in OS (HR: 2.50, 95%CI: 1.1-5.2, P = 0.01). In our study, a high PLR and low serum albumin level were statistically significant based on univariate analysis (P = 0.05 and P = 0.01, respectively) (Table 3). Although DFS was shorter in patients with a BMI < 25 kg/m² than in those with a BMI ≥ 25 kg/m², the difference was not statistically significant (18.5 months vs. not reached, P = 0.61) (Table 2). However, excess weight of (> 20%) has been associated with increased surgical mortality and morbidity[25].

Among patients in this study, 82 (46.3%) had stage 3 cancer. Tumor responses were better in patients with early-stage disease than in those with > T2 or higher tumors[14]. The number of patients with early-stage disease in this study was only six (12.7%), which was not statistically significant (P = 0.06), and the response rate in this group was 8%[14,26]. In addition to the tumor RS, lymphovascular invasion, perineural invasion, and signet-ring cell pathology were associated with a poor prognosis[23,26]. Furthermore, the R0 resection rate was lower (83%) in our patients, presumably because 69% of patients had cT3-4 tumors, indicating a high tumor burden. No standard cut-off values exist for the NLR and PLR[19]. Cut-off values identified in this study were lower than those reported in the literature. Additionally, data regarding neutrophil count, platelet count, lymphocyte count, and albumin level represented a small sample group, limiting our ability to assess the inflammatory response. Preoperative blood transfusion history and out-of-hospital antibiotic use were not clearly defined. The tumor-node-metastasis classification system was used; however, it could not differentiate between diffuse and intestinal-type tumors or linitis plastica, which may have contributed to the unfavorable prognosis.

CONCLUSION

Among patients with gastric cancer who received neoadjuvant chemotherapy, preoperative serum NLR and PLR did not demonstrate prognostic significance. OS was suboptimal in patients with microscopic residual disease at the conclusion of surgery, those who were unable to complete perioperative chemotherapy, and those with hypoalbuminemia. Poor nutritional status, substantial tumor burden, and inadequate tumor response contributed to the poor prognosis observed in this study.

ACKNOWLEDGEMENTS

We thank our colleagues who have cooperated in this study.