The Effect of Albumin Value, HALP Score and LCR Value on Predicting Survival and Recurrence in Patients with Pancreatic Adenocancer

doi:10.21203/rs.3.rs-4986057/v1

Download PDF

Article

The Effect of Albumin Value, HALP Score and LCR Value on Predicting Survival and Recurrence in Patients with Pancreatic Adenocancer

https://doi.org/10.21203/rs.3.rs-4986057/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Aim

The aim of this study is to investigate whether the albumin value and the ratios of biochemical markers; hemoglobin, albumin, lymphocyte and platelet (HALP score) and lymphocyte-C-reactive protein ratio (LCR) can predict the survival and recurrence of the disease in patients with pancreatic adenocarcinoma.

Materials and Methods

Patients operated for pancreatic adenocarcinoma (n:87) who did not receive neoadjuvant treatment in our clinic between January 2017 and December 2021 were included in the study. The preoperative albumin levels, HALP scores and LCR values were calculated, and analyzed to determine whether the differences in these ratios could predict pathological findings in the early period.

Results

The average age of 87 patients included in our study was 64.8 ± 9.6 years. 59 (67.8%) of the patients were male and 28 (32.2%) were female. The cut-off value for HALP score was determined as 34.4, the cut-off value for LCR value was 0.61, and the cut-off value for albumin value was 38.55. It was found that the overall survival time of patients with low HALP scores was significantly shorter than patients with high HALP scores (15.8 vs. 19.3 months) (p < 0.01). The overall survival time of patients with low LCR was significantly longer (17.8 vs 18.5 months) than patients with high LCR score (p < 0.01). The overall survival time of patients with high albumin values was found to be significantly longer (14.6 vs 16.3 months) than patients with low albumin values (p < 0.01).

Conclusion

Low HALP levels and low albumin values were confirmed to be significant independent prognostic factors for disease-free survival and overall survival in pancreatic adenocarcinoma patients.

Biological sciences/Cancer/Gastrointestinal cancer/Pancreatic cancer

Biological sciences/Biochemistry

Pancreatic adenocancer

albumin

hemoglobin

lymphocyte

platelet

Pancreatic adenocarcinoma represents one of the most lethal and aggressive types of cancer. Pancreatic cancer is a highly malignant solid tumor with a 1-year overall survival rate of 26% and a 5-year survival rate of less than 5% [1]. According to American Cancer Society 2022 data, pancreatic adenocarcinomas account for 3% of cancers and 7% of cancer-related deaths in the USA. Every year, 2 thousand patients are newly diagnosed with similar incidence in both male and female. Its incidence increases with age. Although great efforts have been made in early diagnosis and treatment, the prognosis of this disease remains poor [2]. Because the pancreas is a retroperitoneal organ, pancreatic cancers are usually diagnosed at late stages, and therefore its mortality and morbidity rates are poor. Especially high relapse rates also increase mortality and morbidity [3]. Pancreatic cancer is caused by a combination of genetic and environmental risk factors. Risk factors include gender, age, race, diabetes mellitus (DM), family history of pancreatic cancer, familial syndromes that may cause genetic predisposition, and smoking.

There is a strong relationship between the cancer development process and the systemic inflammatory response. The degree of systemic inflammatory response measured before surgery is associated with survival in patients with cancer. Whatever the cause behind systemic inflammation, it contributes to cancer development through effects such as increasing resistance to apoptosis around the tumor and stimulating angiogenesis [4, 5]. With regard to this correlation, biochemical markers of inflammatory response, including albumin and C- reactive protein (CRP), have been proposed as prognostic indicators in solid cancers originating from various organs [6]. Hemoglobin, leukocyte and platelet counts are also known as factors that determine the prognosis of cancer patients [7, 8]. Serum albumin is the most abundant blood plasma protein in humans and is produced by the liver. Albumin is also an important prognostic factor in oncological patients, hypoalbuminemia has been shown indicate a poor prognosis [9]. Prognostic factors like lymphocyte-CRP ratio (LCR) and hemoglobin, albumin, lymphocyte and platelet (HALP score) have been derived through combinations of these parameters that are obtainable through blood counts [10]. LCR is a ratio of lymphocytes and CRP levels and has been used as a prognostic factor in various cancers [11]. A low HALP score, which is the combination of hemoglobin, albumin, lymphocyte and platelet counts has been shown to be another sign of poor prognosis in cancer [11, 12, 13].

To our knowledge, there is no study in the literature has investigated the relationship between albumin, HALP score, LCR and survival and recurrence in pancreatic adenocarcinomas. Preoperative HALP and LCR values were calculated from laboratory data after retrospective review of patients operated for pancreatic adenocarcinoma in our clinic. Furthermore, clinical follow-ups of these patients were conducted to access survival and recurrence data. Efforts were made to elucidate the relationships between calculated albumin, HALP, and LCR values derived from these data.

The study included 87 patients who underwent either pancreaticoduodenectomy (Whipple or total pancreatectomy) operations for pancreatic adenocarcinoma in the General Surgery Clinic of Ege University Hospital between January 2017 and December 2021. The data of the patients were obtained from the electronic medical records of the hospital and analyzed retrospectively. Ethics committee approval was received from the University Ethics Committee Commission (dated 23.03.2023 and Decision No: 23-3.1T/31).

Adult patients (over 18 years of age) who underwent Whipple operation and total pancreatectomy due to pathologically confirmed pancreatic adenocarcinoma were included in the study. Patients receiving neoadjuvant therapy, patients with incomplete clinicopathological and follow-up data, and patients with other malignant tumors (choledochal tumor, papilla tumor and duodenal tumor) were excluded from the study.

Patients were routinely followed until death due to disease relapse in accordance with a standardized protocol. Each patient was checked with clinical and laboratory examinations once a month or at longer intervals after surgery. If local or metastatic recurrence was suspected, imaging studies (computed tomography scans, magnetic resonance imaging, bone scans, or positron emission tomography/computed tomography) were recommended accordingly. Overall survival was defined as the time from surgery to death or last follow-up visit. Disease-free survival was defined as the time from surgery to tumor recurrence or last follow-up visit.

Inflammation markers such as HALP score and LCR value were obtained using biochemical parameters.

HALP score calculation

Hemoglobin (gr/dL) x Albumin (gr/dL) x Lymphocyte (count/µl) / Platelet (count/µl).

LCR calculation

Lymphocytes (counts/µl) / CRP (mg/L).

Statistical analysis

SPSS 24 statistical software package (Statistical Package for the Social Sciences – IBM®) was used to analyze the data collected in the study. Descriptive statistics regarding the distribution of responses to independent variables in the study are presented as numbers and percentages for categorical variables, and as mean, standard deviation and median for numerical variables. The compliance of continuous variables with the normal distribution assumption was evaluated with the Kolmogorov-Smirnow test. For pairwise and multiple comparisons, Chi-square test, Fisher exact test were used for categorical variables, Independent t-test, One Way Anova test or Kruskal-Wallis Method was used for quantitative variables. The cutoff value with the minimum P value calculated from the log-rank χ2 test for overall survival was determined as the optimal cutoff value.

ROC (Recipient Operating Characteristic) analysis was used to determine whether HALP and LCR values were prognostic indicators for clinical and pathological response prediction. The area under the ROC curves (AUC) values obtained as a result of ROC analysis were evaluated as 0.9-1: excellent, 0.8–0.9: good, 0.7–0.8: moderate, 0.6–0.7: poor and 0.5–0.6: unsuccessful. In ROC analysis, the best cut-off point (maximum sensitivity and specificity) was determined. Sensitivity, specificity, positive-negative predictive values (PPV, NPV) and likelihood ratio (+) values were calculated to evaluate the success of the cut-off points determined after ROC analysis. The log-rank test was used to compare Kaplan-Meier survival curves. Log-rank tests were performed to compare patient survival between subgroups. Multivariable Cox regression survival analyzes were performed to determine the independent association of all clinical features with survival. The results were evaluated at 95% confidence interval and p < 0.05 was considered significant.

Clinical features and survival and mortality characteristics of patients

The clinical characteristics of the 87 patients are described in Table 1. The average age was 64.8 ± 9.6 (range, 41–109). 59 (67.8%) of the patients were male and 28 (32.2%) were female. The average survival time of the patients was 15.6 ± 10.6 months (range, 1–45) and the average disease-free survival time was 13.5 ± 15.5 (range, 0–72) months.

The average hemoglobin value of the patients was 12.8 ± 1.7 (range, 8.4–17.1), the average albumin value was 39.7 ± 5.3 (range, 26.4–51.0), the average lymphocyte value was 1914, 7 ± 846.1 (µL) (range, 400–4780), mean platelet value 274413.8 ± 87668.7 (µL) (range, 124000–614000) and mean CRP value 18.8 ± 24.1 (mg/L) (range, 0.3–99, 3) was found to be.

While the average HALP score of the patients was 38.8 ± 22.3 (range, 5.9-132.2), their average LCR score was observed to be 0.66 ± 1.34 (range, 0.01–9.57).

The average number of metastatic lymph nodes in all patients was determined to be 22.3 ± 11.6 (range, 0–58). Mortality occurred in 72 (82.8%) patients during follow up period. Of a total of 87 patients, 57 (65.5%) received adjuvant chemotherapy and 1 (1.1%) received radiotherapy.

When TNM classification of the tumors are examined; It was observed that 15 (17.2%) were in the T1 stage, 45 (51.7%) were in the T2 stage, 17 (19.5%) were in the T3 stage, and 10 (11.5%) were in the T4 stage. When the N stages of the patients are examined; It was observed that 20 (23.0%) were in the N0 stage, 31 (35.6%) were in the N1 stage, and 36 (41.4%) were in the N2 stage. In the pathology of patients; it was observed that 12 (13.8%) had poor differentiation, 69 (79.3%) had moderate differentiation, and 6 (7%) had good differentiation. There was perineural invasion in 69 (79.3%) of the patients, lymphovascular invasion in 40 (46.0%), and local soft tissue invasion in 70 (80.5%) patients. (Table 1)

Table 1

Clinicopathological characteristics of pancreatic adenocarcinoma patients, n (%)
Proporties	n:87
Age (year, mean ± std, min-max)	64,8 ± 9,6 (41–109)
Gender (male/female)	59 (%67,8)/ 28 (%32,2)
Survival (month, mean ± std, min-max)	15,6 ± 10,6 (1–45)
Disease-free Survival (month, mean ± std, min-max)	13,5 ± 15,5 (0–72)
Hemoglobin (mean ± std, min-max)	12,8 ± 1,7 (8,4–17,1)
Albumin (mean ± std, min-max)	39,7 ± 5,3 (26,4–51,0)
Lymphocyte (mean ± std, min-max)	1914,7 ± 846,1 (400–4780)
Platelet (mean ± std, min-max)	274413,8 ± 87668,7 (124000–614000)
CRP (mean ± std, min-max)	18,8 ± 24,1 (0,3–99,3)
HALP score	38,8 ± 22,3 (5,9-132,2)
LCR value	0,66 ± 1,34 (0,01–9,57)
Lymph node (mean ± std, min-max)	22,3 ± 11,6 (0–58)
Mortality (yes/no)	72 (%82,8)/ 15 (%17,2)
Tstage (1 stage /2stage/ 3 stage / 4stage)	15 (%17,2) / 45(%51,7) /17 (%19,5)/ 10 (%11,5)
N stage (0 stage /1stage/ 2 stage )	20 (%23,0)/ 31 (%35,6)/ 36 (%41,4)
PRSM (yes/no)	35 (%40,2)/ 52(%59,8)
Differentiation (Poor/Little/Middle/Well)	1(%1,1)/ 12 (%13,8)/ 69(%79,3)/ 5(%5,7)
Perineural invasion (yes/no)	69 (%79,3)/ 18 (%20,7)
Lymphovascular invasion (yes/no)	40 (%46,0)/ 47(%54,0)
Local soft tissue invasion (yes/no)	70 (%80,5)/ 17(%19,5)
Adjuvant Chemotherapy (yes/no/ radiotherapy)	57 (%65,5)/ 29 (%33,3)/ 1 (%1,1)

Abbreviations: PRSM :positive retroperitoneal surgical margin, T: tumor, N:lymph node

Relationship between albumin, HALP score and LCR value and clinical features

The sensitivity, selectivity, positive-negative predictive values and likelihood ratio (+) values calculated regarding the classification success of HALP values in response prediction according to the cut-off values determined as a result of ROC analysis of pancreatic adenocarcinoma patients are presented in Table 2–3 and Fig. 1. For patients with pancreatic adenocarcinoma, the cut-off point for albumin value was 38.55, the cut-off point for HALP value was 34.4, and the cut-off point for LCR value was 0.61. Classification success for this cut-off point; In patients with pancreatic adenocarcinoma, the sensitivity for the HALP score was found 89.3% and the specificity was 55.6%, the sensitivity for the LCR question was 79.8% and the specificity was 64.3%, and the sensitivity for the albumin value was 88.6% and the specificity was 78.8%.

Table 2

Cut-off values and sensitivity results for albumin value, HALP score and LCR value of patients with pancreatic adenocarcinoma
	With pancreatic adenocarcinoma- HALP	With pancreatic adenocarcinoma- LCR	With pancreatic adenocarcinoma- Albumin
AUC (95% CI)	0.655 (0.518–0.791)	0.771 (0.664–0.877)	0,826 (0,657-0,994)
P values	0.034	< 0.001	0,028
Cut off	34,41	0,61	38,55
Sensitivity (95% CI)	89.3% (63,5-98.5)	79,8% (62.2–97.9)	88,6% (69,7–99,3)
Specificity (95% CI)	55,6% (32.1–65.9)	64,3% (51-78.2)	78,8% (61,2–82,7)
PPV (95% CI)	26.8% (16.5–41.1)	37.5% (22.5–53)	34,2% (20,1–48,9)
NPV (95% CI)	94.9% (77.3–98.9)	96.7% (85.2–99.2)	95,4% (78,4–97,8)
LR+ (95% CI)	1.66 (1.18–2.14)	2.51 (1.59–3.32)	1,78% (1,21 − 2,85)

ROC: Receiver Operating Characteristic, PPV: positive predictive value, NPV: negative predictive value,

AUC: Area under curve, CI: Confidence interval, HALP: Hemoglobin, albumin, lymphocyte, and platelet; LCR: lymphocytes and CRP. LR+: Likelihoods Ratio

Table 3

ROC analyses of albumin, HALP score and LCR score.
Test Result Variable(s)	Area	Std. Error^a	Asymptotic Sig.^b	Asymptotic 95% Confidence Interval
Test Result Variable(s)	Area	Std. Error^a	Asymptotic Sig.^b	Lower Bound	Upper Bound
HALP SCORE	0,590	0,070	0,017	0,452	0,727
LCR VALUE	0,490	0,066	0,048	0,361	0,619
ALBUMIN VALUE	0,582	0,792	0,032	0,428	0,736
a. Under the nonparametric assumption. b. Null hypothesis: true area = 0.5

The cut-off value of HALP score was set as 34.4, providing the optimal classification for survival prediction. Low levels of HALP scores were present in 42 patients. While the averages of age, disease-free survival, platelet and CRP levels of patients with low HALP scores were higher than the high HALP group, their survival times, hemoglobin, albumin, lymphocyte and average lymph node numbers were lower than the high HALP score group.HALP score averages, survival (p = 0.048), disease-free survival (p = 0.032), Hb (p < 0.01), albumin (p < 0.01), lymphocyte (p < 0.001), platelet (p = 0.006). It was observed that there were significant differences between CRP (p = 0.036) and resected lymph node (p = 0.027). In addition, high HALP score was significantly associated with the patients being male, T1-2 stages, N1-2 stages, and receiving adjuvant chemotherapy (p < 0.05).(Table 4)

Table 4

Relationship between HALP score and clinical features
Variables	HALP		p
Variables	Low (≤ 34,4, n:42)	High (> 34,4, n:45)	p
Age (year, mean ± std)	65,7 ± 8,1	63,9 ± 10,9	0,379
Survival (month, mean ± std)	15,8 ± 19,1	19,3 ± 11,1	0,048*
Disease-free Survival (month, mean ± std,)	13,4 ± 9,0	17,7 ± 11,8	0,032*
Hemoglobin (mean ± std)	12,3 ± 1,7	13,5 ± 1,3	< 0,001*
Albumin (mean ± std)	37,2 ± 5,3	42,0 ± 4,2	< 0,001*
Lymphocyte (mean ± std,)	1456,0 ± 592,6	2342,9 ± 826,8	< 0,001*
Platelet (mean ± std)	300.714,3 ± 94.742,1	249.866 ± 73.359	0,006*
CRP (mean ± std)	24,4 ± 25,0	13,6 ± 22,3	0,036*
Lymph node (mean ± std)	19,1 ± 9,3	24,1 ± 13,2	0,027*
Gender (male/female)	26/16	33/12	0,018*
Mortality (yes/no)	36/6	36/9	0,338
T stage (1 stage /2 stage/ 3 stage / 4 stage)	10/21/7/4	5/24/10/6	0,017*
N stage(0 /1/ 2 )	12/17/13	8/14/23	0,046*
PRSM (yes/no)	15/27	20/25	0,271
Differentiation (Poor/Little/Middle/Well)	0/5/33/4	1/7/36/1	0,367
Perineural invasion (yes/no)	34/8	35/10	0,461
Lymphovascular invasion (yes/no)	21/21	19/260,304	0,204
Local soft tissue invasion (yes/no)	33/9	37/8	0,436
Adjuvant Chemotherapy (yes/no/radiotherapy) (n:87)	25/16/1	32/13/0	0,012*

(One way ANOVA test, Chi square test, independent test, p < 0.05 significance)

The cut-off value of LCR was set at 0.61, which provided the best classification for survival prediction. Low-level LCR was present in 70 patients. While the survival times, platelet, CRP levels and average number lymph nodes of patients with low LCR levels were higher than the high LCR group, their average age, disease-free survival time, hemoglobin, albumin and lymphocyte average numbers were observed to be lower than the high LCR group. It was observed that there were significant differences between the average valus of LCR and survival (p = 0.041), disease-free survival (p = 0.042), lymphocyte (p = 0.004), platelet (p = 0.008) and CRP levels (p < 0.001). In addition, the LCR score was significantly associated with patients being male, developing mortality, being in the T2-3 stages, being in the N1-2 stages, and receiving adjuvant chemotherapy (p < 0.05).

Low LCR level was significantly associated with levels of perineural invasion, lymphovascular invasion, and surrounding soft tissue invasion ( P < 0.05).(Table 5)

Table 5

Relationship between LCR value and clinical features
Variables	LCR		p
Variables	Low (≤ 0,61, n:70)	High (> 0,61, n:17)	p
Age (year, mean ± std)	64,0 ± 7,9	68,9 ± 14,7	0,141
Survival (month, mean ± std)	17,8 ± 11,0	18,5 ± 8,6	0,041*
Disease-free Survival (month, mean ± std,)	12,8 ± 12,8	16,3 ± 14,5	0,042*
Hemoglobin (mean ± std)	12,7 ± 1,7	13,0 ± 1,4	0,437
Albumin (mean ± std)	37,3 ± 5,4	41,2 ± 4,7	0,181
Lymphocyte (mean ± std,)	1788,6 ± 770,4	2434,1 ± 965,5	0,004*
Platelet (mean ± std)	286.571,4 ± 88.428,7	224.352,9 ± 65418,8	0,008*
CRP (mean ± std)	23,0 ± 25,2	11,5 ± 0,8	< 0,001*
Lymph node (mean ± std)	22,4 ± 11,2	21,6 ± 13,4	0,654
Gender (male/female)	46/24	13/4	0,023*
Mortality (yes/no)	58/12	14/3	0,012*
T stage (1 /2/ 3 / 4)	14/37/13/6	1/8/4/4	0,029*
N stage (0 /1 / 2 )	15/22/33	5/9/3	0,031*
PRSM (yes/no)	29/41	6/11	0,430
Dıfferentıatıon (Poor/Little/Middle/Well)	1/8/57/4	0/4/12/1	0,267
Perineural invasion (yes/no)	56/14	13/4	0,048*
Lymphovascular invasion (yes/no)	33/37	7/10	0,038*
Local soft tissue invasion (yes/no)	59/11	11/6	0,041*
Adjuvant Chemotherapy (yes/no/radiotherapy) (n:87)	50/19/1	7/10/0	0,034*

(One way ANOVA test, Chi square test, independent test, p < 0.05 significance)

The cut-off value for albumin was set at 38.55, providing the best classification for survival prediction. 35 patients had low levels of albumin. While the average age, platelet and CRP values of patients with low albumin values were higher than those of patients with high albumin values, it was observed that disease-free survival time, survival times, hemoglobin, lymphocyte and lymph node average numbers were lower than those of patients with high albumin values. It was determined that there were significant differences between the albumin value averages and survival (p = 0.043), disease-free survival (p = 0.017), Hb (p < 0.01), and lymphocyte count (p = 0.013). Moreover, low albumin value level was significantly associated with peri neural, peri vascular and local soft tissue invasion levels (P < 0.05). (Table 6)

Table 6

Relationship between albumin value and clinical features
Variables	ALBUMIN		p
Variables	Low (≤ 38,55, n:35)	High (> 38,55, n:52)	p
Age (year, mean ± std)	65,2 ± 7,3	64,5 ± 11,0	0,748
Survival (month, mean ± std)	14,6 ± 9,1	16,3 ± 11,8	0,043*
Disease-free Survival (month, mean ± std,)	10,0 ± 11,6	15,7 ± 17,3	0,017*
Hemoglobin (mean ± std)	11,8 ± 1,7	13,4 ± 1,3	0,001*
Lymphocyte (mean ± std,)	1739,1 ± 722,2	2032,9 ± 907,8	0,013*
Platelet (mean ± std)	277400,0 ± 71123,4	272403,8 ± 97866,1	0,796
CRP (mean ± std)	20,2 ± 21,3	17,9 ± 26,0	0,671
Lymph node (mean ± std)	21,1 ± 10,0	23,1 ± 12,6	0,446
Gender (male/female)	12/23	16/36	0,454
Mortality (yes/no)	4/31	11/41	0,188
T stage (1 stage /2stage/ 3 stage / 4stage)	5/20/8/2	10/25/9/8	0,319
N stage (0 stage /1stage/ 2 stage )	7/13/15	13/18/21	0,862
RPTM (yes/no)	22/13	30/22	0,399
Dıfferentıatıon (Poor/Little/Middle/Well)	4/29/1/1	8/40/4/0	0,388
Perineural invasion (yes/no)	5/30	13/39	0,017*
Lymphovascular invasion (yes/no)	18/17	29/23	0,042*
Surrounding soft tissue invasion (yes/no)	5/30	12/40	0,023*
Adjuvant Chemotherapy (yes/no/radiotherapy) (n:87)	16/19/0	41/10/1	0,038*

According to the results of Kaplan Meier analysis; it was found that the overall survival time of patients with low HALP scores was significantly longer (15.8 months) than patients with high HALP scores (19.3 months) (p < 0.01). In addition, it was found that the overall survival time of patients with low LCR score was significantly longer (17.8 months) and that of patients with high LCR score was significantly longer (18.5 months) (p < 0.01). In addition, it was determined that the overall survival time of patients with low albumin value was significantly longer (14.6 months) and that of patients with high albumin value was significantly longer (16.3 months) (p < 0.01).

According to the results of Kaplan Meier analysis; it was found that the disease-free survival time (13.4 months) of patients with low HALP scores was significantly shorter (17.7 months) than patients with high HALP scores (p < 0.01). In addition, it was observed that the disease-free survival time of the patients (12.8 months) was significantly shorter (16.3 months) than that of patients with high LCR scores (p < 0.01). In addition, it was determined that the disease-free survival time (11.8 months) of patients with low albumin values was significantly longer (15.7 months) than patients with high albumin values (p < 0.01).

It was observed that low HALP level, low albumin value and high LCR level were independent risk factors for early recurrence and short survival, regardless of gender, tumor stage and other variables.

In univariate analysis, age, differentiation, tumor size, T stage, N stage, Metastatic LN and Lymphovascular invasion predicted survival (p < 0.05).

Univariate Cox regression analysis showed that albumin, LCR and HALP levels were all associated with median overall survival time (Table 6). According to the result of multivariate Cox regression analysis, HALP score showed that it was an independent favorable factor for overall survival [HR = 2.367, 95% confidence interval (CI): 1.174–2.357, P < 0.001]. Additionally, LCR values was observed to be an independent positive factor for overall survival [HR = 1.188, 95% confidence interval (CI): 1.023–1617, = 0.012]. Moreover, it showed that albumin value was an independent favorable factor for overall survival [HR = 2.796, 95% confidence interval (CI): 1.878–4.286, P < 0.025]. (Table 7)

Table 7

Univariate and multivariate Cox analysis for overall survival
	Univariate analysis
Variable	HR(95%CI)	P value	HR(95%CI)	P value
Univariateanalysis
Age	1.361 (1,036 − 1,681)	0.012	-	-
Sex.female vs male	0.789 (0.562–1.265)	0,478	-	-
Adjuvant Chemotherapy	1.221 (0.912–1.668)	0.23	1,067 (0.912–2,388)	0.231
Mortality	3.635 (2.321–5.684)	0.033	2,840 (0,915-4,671)	< 0.001
Lymph node	1.856 (1.047–2.190)	0,047	1.719 (1.427–1.915)	< 0.001
CRP	1.775 (1.365–2.215)	0,043	1.687(1.380–2.165)	< 0.001
Antrum	1.473 (1.175–1.876)	0.423	1.264 (1.135–1.387)	0,009
Diferantiation	1.856 (1.241–2.732)	0.003	1.319 (0.982–1.862)	0,024
T Stage	2.894 (1.787–5.265)	0.014	2.478 (1.258–4.775)	0,037
N Stage HALP score ((≤ 34,4/>34,4) LCR score (≤ 0,61/>0,61)	1.935 (1.125–2.092) 2,635 (1.712–3.029) 1.226 (1.068–1.681)	0.014 < 0.001 0,006	1.512 (1.157–1.913) 2,367 (1,174-2.357) 1.188 (1,023-1617)	0,022 < 0.001 0,012
Albumin (≤ 38,55/ >38,55)	2,147 (1.536–2.489)	0,013	2,796 (1,878–4,286)	0,025
Positive retroperiton surgical margin	3.852 (1.836–7.910)	< 0.001	3,589(1,940–6,539)	< 0.001
Local soft tissue invasion	2.284 (1.24–4.18)	0.008	3.412 (2.111–4.216)	< 0.001
Lymphovascular invasion	2.367 (1.487–3.711)	< .001	2.158 (1.517–2.943)	0,415
Perineural invasion	1.892 (0.987–2.822)	0.521	1.632(1.365–2.573)	0,352

Many studies have been conducted and prognostic factors have been studied predict the prognosis of patients with pancreatic adenocarcinoma. Unfortunately, no marker that can be used in daily clinical practice has been found. Many studies have shown that hemoglobin levels affect survival in patients with malignancies [14]. It is widely accepted that the systemic inflammatory response is associated with the prognosis of cancer patients [15, 16]. Inflammatory markers obtained from biochemical results such as hemogram, albumin and CRP values, which are inexpensive routinely tested in patients and are used as markers in many diseases. Recent studies have identified a new marker, the HALP score, consisting of hemoglobin, albumin, lymphocytes, and platelets, reflecting both systemic inflammation and nutritional status. Previous studies have reported that it is associated with survival in patients with stomach[17], colorectal [18], kidney[19] and bladder cancer[20]. Models based on HALP score and LCR values have been shown to effectively identify patients with high survival risk in malignancies. However, there are very few studies investigating the relationship between HALP and survival after radical resection in patients with pancreatic cancer. Therefore, the aim of this study was to examine the correlation between the HALP score and LCR values with survival and recurrence in patients with pancreatic adenocarcinoma.

Albumin is a negative acute phase reactant synthesized in the liver. Hypoalbuminemia may result from malnutrition, hypercatabolism caused by cancer cells, and increased inflammation due to cytokine release, which plays a role in the survival of cancer patients. It is also widely used in various neoplastic diseases as a prognostic score for patients with sepsis. Serum albumin and hemoglobin levels, as a measurable continuous variable, are some of the most commonly used indicators of a patient's nutritional status and are also used to assess cancer progression and prognosis. Decrease in serum albumin levels after surgery is an indicator of stress response. Therefore, reducing postoperative surgical stress may result in optimal early recovery of postoperative serum albumin levels. In fact, low albumin and hemoglobin levels are associated with poor survival of cancer patients [21–24]. In our study, the cut-off value of albumin for patients with pancreatic adenocarcinoma was determined as 38.55. It was found that the overall survival time of patients with low albumin value was significantly longer (14.6 months) and that of patients with high albumin value was significantly longer (16.3 months) (p < 0.01). In addition, it was determined that the disease-free survival time of patients with low albumin value was significantly longer (11.8 months) and that of patients with high albumin value was significantly longer (15.7 months) (p < 0.01).

Lymphocytes inhibit apoptosis by secreting TNF alpha and interferon gamma and contribute to long-term survival by preventing tumor migration and invasion. Lymphopenia is also frequently observed in advanced cancer patients and stimulates cancer progression [25, 26]. Platelets play an important role in cancer formation and prognosis by increasing angiogenesis, migration and vascular permeability through growth factors. Metastasis is associated with platelet stimulation [27], and platelets protect cancer cells from immunological attack [28]. HALP is the integration of these four hematological parameters and has shown prognostic value for cancer patients [29].

The average survival time of all patients in our study was 15.6 ± 10.6 months (range, 1–45) and the average disease-free survival time was 13.5 ± 15.5 (range, 0–72) months. The general characteristics and median survival times of the patient population in our study were found to be compatible with the literature [30].

In our study, the cut-off value of HALP for patients with pancreatic adenocarcinoma was determined as 34.4 and the cut-off value for LCR was 0.61. As a result of our study, it was determined that the overall survival time (15.8 months) of patients with low HALP scores was significantly shorter (19.3 months) than patients with high HALP scores (p < 0.01). In addition, another result we obtained from our study was that the disease-free survival time (13.4 months) of patients with low HALP scores was significantly shorter (17.7 months) than patients with high HALP scores (p < 0.01).

The median overall survival of the HALP-low group was shorter than the high HALP group, and this difference was statistically significant (p < 0.001). In this study, it was seen that a high HALP score was a good prognostic indicator and our study was compatible with the literature. [31, 32, 33].

There are many studies in the literature highlighting the prognostic importance of the HALP score. For example, a study involving 582 patients with resectable pancreatic cancer showed that a high preoperative HALP score was identified as a prognostic factor for survival [34]. According to a study involving 355 patients diagnosed with esophageal squamous cell carcinoma, a high preoperative HALP score was identified as an independent and favorable prognostic indicator [35]. In a separate study by Topal et al., including 110 colorectal cancer patients who underwent surgery, it was observed that the prognostic significance of a low HALP score decreased in the presence of tumor budding [36]. Again, in a study in which 591 patients with locally confined gastrointestinal stromal tumors were followed after surgery, a low HALP score predicted short disease-free survival [37]. Ekinci et al. In a study of 123 patients diagnosed with metastatic renal cell carcinoma, low HALP score was associated with poor prognosis [32]. In a study conducted on 204 patients with stomach cancer, they reported that a low HALP score numerically indicated a poor prognosis [31].

LCR, as a marker of inflammatory response, is safely used to predict disease-free survival and overall survival rates in patients diagnosed with colorectal cancer and gastric cancer. Low preoperative LCR values have been shown to be associated with worse overall survival and disease-free survival and with more advanced cancer stage [38, 39].

The limitations of our study are a retrospective and single-center study and the patient populations is small. However, the lack of a similar study comparing HALP and LCR inflammatory markers together for recurrence and survival in pancreatic adenocarcinoma patients increases the value of the study. Prospective studies with larger patient series are needed to confirm and standardize the data.

HALP and LCR measured preoperatively are effective cofactors in predicting postoperative overall survival and recurrence in pancreatic adenocarcinoma patients. However, we can conclude from our study that we can predict overall survival just by looking at the albumin value. It may be useful to use these inflammatory markers in conjunction with other diagnostic tools. Therefore, more specific, prospective, well-designed studies with a larger patient population are needed to investigate this issue in more detail.

Ethics approval and consent to participate

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards

Ethics committee approval was received from the University Ethics Committee Commission (dated 23.03.2023 and Decision No: 23-3.1T/31).

Consent for publication

Informed consent was obtained from all participants in the study. Patients signed an informed consent before surgery for dataset use and for figures.

Competing interests

All Authors declare that they have no competing interests.

Funding

This research received no specific Grant from any funding agency in the public, commercial, or not-profit sectors.

Data Availability

The datasets used and analysed during the current study available from the corresponding author on reasonable request.

Acknowledgements

We would like to express our sincere thanks to Prof.Dr. Osman Abbasoglu for his support and constructive feedback on our study.

Rights and permissions

We (all of the authors) have agreed to allow full access to the primary data and to allow the journal to review the data if requested.

The content of this manuscript has not been published or submitted for publication elsewhere.

All authors have made a significant intellectual contribution to this manuscript.

Strobel, O., Neoptolemos, J., Jäger, D. & Büchler, M. W. Optimizing the outcomes of pancreatic cancer surgery. Nat. Rev. Clin. Oncol. 16, 11–26. 10.1038/s41571-018-0112-1] (2019). [PMID: 30341417.
van Roessel, S. et al. International Validation of the Eighth Edition of the American Joint Committee on Cancer (AJCC) TNM Staging System in Patients With Resected Pancreatic Cancer. JAMA Surg. 153 10.1001/jamasurg.2018.3617] (2018). e183617 [PMID: 30285076.
Stone, M. L. & Beatty, G. L. Cellular determinants and therapeutic implications of inflammation in pancreatic cancer. Pharmacol. Ther. 201, 202–213. 10.1016/j.pharmthera.2019.05.012] (2019). [PMID: 31158393.
Allavena, P., Garlanda, C., Borrello, M. G., Sica, A. & Mantovani, A. Pathways connecting inflammation and cancer. Curr Opin Genet Dev. ;18(1):3–10. doi: (2008). 10.1016/j.gde.2008.01.003. Epub 2008 Mar 5. PMID: 18325755.
Shacter, E. & Weitzman, S. A. Chronic inflammation and cancer. Oncology (Williston Park). ;16(2):217 – 26, 229; discussion 230-2. PMID: 11866137. (2002).
Clarke, S. J. et al. Use of inflammatory markers to guide cancer treatment. Clin. Pharmacol. Ther. 90 (3), 475–478. 10.1038/clpt.2011.122 (2011).
Caro, J. J., Salas, M., Ward, A. & Goss, G. Anemia as an independent prognostic factor for survival in patients with cancer: a systemic, quantitative review. Cancer. 91 (12), 2214–2221 (2001).
Jurasz, P., Alonso-Escolano, D. & Radomski, M. W. Platelet–cancer interactions: mechanisms and pharmacology of tumour cell-induced platelet aggregation. Br. J. Pharmacol. 143 (7), 819–826. 10.1038/sj.bjp.0706013 (2004).
Oñate-Ocaña, L. F. et al. Serum albumin as a significant prognostic factor for patients with gastric carcinoma. Ann. Surg. Oncol. 14 (2), 381–389. 10.1245/s10434-006-9093-x (2007). Epub 2006 Dec 9. PMID: 17160496.
Roxburgh, C. S. & McMillan, D. C. Role of systemic inflammatory response in predicting survival in patients with primary operable cancer. Future Oncol. 6 (1), 149–163. 10.2217/fon.09.136 (2010).
Lu, L. H. et al. Lymphocyte-C-reactive protein ratio as a novel prognostic index in intrahepatic cholangiocarcinoma: A multicentre cohort study. Liver Int. 41 (2), 378–387. 10.1111/liv.14567 (2021).
Guo, Y. et al. The Hemoglobin, Albumin, Lymphocyte, and Platelet (HALP) Score is a Novel Significant Prognostic Factor for Patients with Metastatic Prostate Cancer Undergoing Cytoreductive Radical Prostatectomy. J. Cancer. 10 (1), 81–91. 10.7150/jca.27210 (2019). Published 2019 Jan 1.
Wang, S. C. et al. Pretreatment Neutrophil to Lymphocyte Ratio Independently Predicts Disease-specific Survival in Resectable Gastroesophageal Junction and Gastric Adenocarcinoma. Ann. Surg. 263 (2), 292–297. 10.1097/SLA.0000000000001189 (2016).
Belcher, D. A. et al. The quaternary state of polymerized human hemoglobin regulates oxygenation of breast cancer solid tumors: A theoretical and experimental study. PLoS One : 13(2), e0191275 (2018).
Lu, H., Ouyang, W. & Huang, C. Inflammation, a key event in cancer development. Mol. Cancer Res. 4, 221–233 (2006).
Rock, C. L. et al. Nutrition and physical activity guidelines for cancer survivors. CA Cancer J. Clin. 62, 243–274 (2012).
Chen, X. L. et al. Prognostic significance of the combination of preoperative hemoglobin, albumin, lymphocyte and platelet in patients with gastric carcinoma: a retrospective cohort study. Oncotarget. 6, 41370–41382. 10.18632/oncotarget.5629] (2015). [PMID: 26497995.
Jiang, H. et al. Preoperative combined hemoglobin, albumin, lymphocyte and platelet levels predict survival in patients with locally advanced colorectal cancer. Oncotarget. 7, 72076–72083. 10.18632/oncotarget.12271] (2016). [PMID: 27765916.
Peng, D. et al. Prognostic significance of the combination of preoperative hemoglobin and albumin levels and lymphocyte and platelet counts (HALP) in patients with renal cell carcinoma after nephrectomy. BMC Urol. 18, 20. 10.1186/s12894-018-0333-8] (2018). [PMID: 29544476.
Guo, Y. et al. The Hemoglobin, Albumin, Lymphocyte, and Platelet (HALP) Score is a Novel Significant Prognostic Factor for Patients with Metastatic Prostate Cancer Undergoing Cytoreductive Radical Prostatectomy. J. Cancer. 10, 81–91. 10.7150/jca.27210] (2019). [PMID: 30662528.
Gupta, D. & Lis, C. G. Pretreatment serum albumin as a predictor of cancer survival: a systematic review of the epidemiological literature. Nutr. J. 9, 69 (2010).
Caro, J. J., Salas, M., Ward, A. & Goss, G. Anemia as an independent prognostic factor for survival in patients with cancer: a systemic, quantitative review. Cancer. 91, 2214–2221 (2001).
Liu, X. et al. Prognostic significance of pretreatment serum levels of albumin, LDH and total bilirubin in patients with non-metastatic breast cancer. Carcinogenesis. 36, 243–248 (2015).
Keeler, B. D. et al. A cohort investigation of anaemia, treatment and the use of allogeneic blood transfusion in colorectal cancer surgery. Ann. Med. Surg. 6, 6–11 (2015).
Ray-Coquard, I. et al. Lymphopenia as a prognostic factor for overall survival in advanced carcinomas, sarcomas, and lymphomas. Cancer Res. 69, 5383–5391 (2009).
Ali, A. A., McMillan, D. C., Matalka, I. I., McNicol, A. M. & McArdle, C. S. Tumour T-lymphocyte subset infiltration and tumour recurrence following curative resection for colorectal cancer. Eur. J. Surg. Oncol. 30, 292–295 (2004).
Nash, G. F., Turner, L. F., Scully, M. F. & Kakkar, A. K. Platelets and cancer. Lancet Oncol. 3, 425–430 (2002).
Stegner, D., Dutting, S. & Nieswandt, B. Mechanistic explanation for platelet contribution to cancer metastasis. Thromb. Res. 2, S149–157 (2014).
Chen, X. L. et al. Prognostic significance of the combination of preoperative hemoglobin, albumin, lymphocyte and platelet in patients with gastric carcinoma: a retrospective cohort study. Oncotarget. 6, 41370–41382. 10.18632/ oncotarget.5629 (2015).
-Ettrich, T. J. & Seufferlein, T. Systemic therapy for metastatic pancreatic cancer. Curr. Treat. Options Oncol. 22 (11), 1–12 (2021).
Sargin, Z. G. & Dusunceli, I. The Effect of HALP Score on the Prognosis of Gastric Adenocarcinoma. J. Coll. Physicians Surg. Pak. 64 (104), 51 (2022).
Ekinci, F., Balcik, O. Y., Oktay, E. & Erdogan, A. P. HALP Score as a New Prognostic Index in Metastatic Renal Cell Cancer. J. Coll. Physicians Surgeons- -Pakistan: JCPSP. 32 (3), 313–318 (2022).
Shen, X. B., Zhang, Y. X., Wang, W. & Pan, Y. Y. The hemoglobin, albumin, lymphocyte, and platelet (HALP) score in patients with small cell lung cancer before firstline treatment with etoposide and progression-free survival. Med. Sci. monitor: Int. Med. J. Experimental Clin. Res. 2019:. 25, 5630
Xu, S. S. et al. Haemoglobin, albumin, lymphocyte and platelet predicts postoperative survival in pancreatic cancer. World J. Gastroenterol. 26 (8), 828 (2020).
Feng, J. F. et al. The preoperative hemoglobin, albumin, lymphocyte and platelet (HALP) score is a useful predictor in patients with resectable esophageal squamous cell carcinoma. Bosnian J. Basic. Med. Sci. 21 (6), 773 (2021).
Topal, U. et al. Diagnostic Value of Preoperative Haemoglobin, Albumin, Lymphocyte and Platelet (HALP) Score in Predicting Tumour Budding in Colorectal Cancer. J. Coll. Physicians Surgeons–Pakistan: JCPSP. 32 (6), 751–757 (2022).
Zhao, Z. et al. Prognostic significance of hemoglobin, albumin, lymphocyte, platelet in gastrointestinal stromal tumors: A propensity matched retrospective cohort study. World J. Gastroenterol. 28 (27), 3476–3487 (2022).
Okugawa, Y. et al. Lymphocyte-C-reactive Protein Ratio as Promising New Marker for Predicting Surgical and Oncological Outcomes in Colorectal Cancer. Ann Surg. ;272(2):342–351. doi: (2020). 10.1097/SLA.0000000000003239. PMID: 32675548.
Okugawa, Y. et al. Lymphocyte-to-C-reactive protein ratio and score are clinically feasible nutrition-inflammation markers of outcome in patients with gastric cancer. Clin. Nutr. 39 (4), 1209–1217 (2020). Epub 2019 May 21. PMID: 31155370.

No competing interests reported.

Download PDF

Version 1

posted

You are reading this latest preprint version

The Effect of Albumin Value, HALP Score and LCR Value on Predicting Survival and Recurrence in Patients with Pancreatic Adenocancer

Status:

Version 1

Abstract

Aim

Materials and Methods

Results

Conclusion

Figures

INTRODUCTION

MATERIAL AND METHOD

Statistical analysis

RESULTS

Clinical features and survival and mortality characteristics of patients

Relationship between albumin, HALP score and LCR value and clinical features

(One way ANOVA test, Chi square test, independent test, p < 0.05 significance)

DISCUSSION

CONCLUSION

Declarations

References

Additional Declarations

Status:

Version 1