Prognostic Value of Baseline Complete Blood Count Components in Advanced Gastric Cancer Patients in Saudi Arabia: A Retrospective Study.

Prognostic value of baseline complete blood count components in advanced gastric cancer

  1. Shereef Elsamany ,
  2. Ahmed Zeeneldin ,
  3. Emad Tashkandi ,
  4. Ayman Rasmy ,
  5. Waleed Abozeed ,
  6. Gomaa Abdelfatah ,
  7. Huda Bukhari ,
  8. Mernan Sulaimani ,
  9. Donia Firaq

Vol 1 No 1 (2020)

DOI 10.31557/apjcc.2020.1.1.1-7

Abstract

Introduction: Several studies assess the prognostic value of biomarkers related to inflammatory response to gastric cancer with inconsistent results.


Objective: This study aims to assess the impact of baseline levels of various components of routine CBC test and other clinico-pathological features on progression free survival (PFS) and overall survival (OS) in metastatic gastric cancer patients.


Methods: This retrospective study included 135 patients with metastatic gastric cancer who presented to 3 hospitals in Saudi Arabia from 2011 to 2016. Various potential prognostic factors were assessed in univariate and multivariate analysis.


Results: After a median follow up of 21.4 months, the median OS and PFS were 11.0 and 6.1 months, respectively. Higher albumin level (> 3 g/dl), low neutrophil percentage ≤ 75%, high lymphocyte percentage > 15%, neutrophil/lymphocyte ≤ 2.5, high eosinophil count >0.4 k/ml, and EOX/EOF chemotherapy vs. doublet chemotherapy were associated with improved PFS in univariate analysis. However, in multivariate analysis, only serum albumin and eosinophil levels were associated with PFS. In univariate analysis, higher serum albumin (3 g/dl), low neutrophil percentage ≤ 75%, high lymphocyte percentage > 15%, neutrophil/lymphocyte ≤ 2.5, high eosinophil count >0.4 k/ml, receiving 1st line chemotherapy vs. no chemotherapy, receiving >6 cycles of chemotherapy, receiving EOX/EOF chemotherapy vs. doublet chemotherapy, platelet count ≤ 450 k/ml, male gender were associated with improved OS. In multivariate analysis, higher serum albumin, lower neutrophil percentage, male gender and higher number of chemotherapy cycles were independently associated with OS.


Conclusion: Higher albumin levels independently predicted better OS and PFS. Higher eosinophil level was associated with improved PFS while lower neutrophil percentage and higher number of chemotherapy cycles were independent predictors of OS.

Introduction

Gastric cancer (GC) is the fourth most common cancer worldwide [1]. Unfortunately, it is usually diagnosed in advanced stages as it is asymptomatic till late in the course of the disease [1]. Generally, it is associated with poor survival outcome and is considered one of the leading causes of cancer-related death worldwide [2].

Several prognostic factors have been proposed including (TNM) stage, and pathological type [3], however, patients’ outcome remains heterogeneous even within the same stage. This highlights the need to develop new biomarkers to refine the prognostic outcome of gastric cancer patients [4][5].

Recently, it was noted that tumour inflammatory response and interaction with the extra-cellular matrix play a crucial role in the tumor micro-environment and are linked to tumor growth and progression [6][7][8]. Several studies displayed significant association of high neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) with adverse outcome in gastric cancer. Noteworthy, these parameters could were suggested to be linked to inflammatory response to the tumour. However, their exact role as prognostic factors is inconsistent among different studies and still not well established [9][10][11][12].

Noteworthy, these parameters can be easily assessed in the routine practice. This makes them attractive enough for further assessment and validation (13). Meanwhile, the prognostic value of absolute count of blood cells including eosinophils and basophils, has rarely been investigated in gastric cancer patients [13][14].

The present study aims to assess the impact of baseline levels of various components of routine complete blood count (CBC) test and other clinico-pathological features on progression free survival (PFS) and overall survival (OS) in metastatic gastric cancer patients. This may aid in developing simple and biologically relevant prognostic factors that may assess in elucidating the expected survival outcome of those patients at baseline.

Materials and Methods

Study population

Patients with histologically confirmed metastatic gastric adenocarcinoma were included. The study group consisted of patients from three centres in Saudi Arabia who were diagnosed from December 2011 to December 2016. Patients who were diagnosed with non-metastatic disease then later on developed metastasis were eligible as well.

Study design and procedures

In this retrospective study, eligible patients must have adequate medical records. Baseline complete blood counts before starting any systemic therapy were recorded including absolute neutrophil count and percentage, absolute lymphocyte count and percentage, neutrophil/lymphocyte ratio, eosinophils, basophils and platelet counts. In addition, different clinico-pathological factors were collected including age, gender, stage at diagnosis, body mass index (BMI), number and sites of metastases, pathological type, grade, HER2 status and serum albumin in addition to treatment data including type and number of chemotherapy cycles. Dates of disease progression and death, if any, were recorded.

Statistical analysis

SPSS version 21 statistical program was used. Descriptive statistics were performed for all clinical, laboratory and pathological data. Different potential prognostic factors were assessed in relation to PFS and OS. Survival data was presented by Kaplan Meier method where cases with no recorded events (death or progression) were censored at the date of last contact. Comparisons of survival outcome among different parameters were made using the log rank test. A two-sided alpha was set at 0.05. Factors with significant association with survival outcome in univariate analysis were assessed via multivariate analysis using Cox proportional hazards model to check for independent prognostic factors. PFS was defined as the time from date of starting first line chemotherapy to date of documented tumour progression or death. OS was defined as the time from the date of diagnosis of metastatic disease till the date of death.

Results

In the present study, 135 patients were included with a median age of 56 years (range: 31-78 years ) with male predominance (66.7%). The gastric body was the commonest primary site (44.7%). Most patients had a single metastatic site (64.5%) with the liver being the commonest (33.3%). First-line chemotherapy was received in 82.2% of patients; however, only 28% received triplet chemotherapy. Adenocarcinoma was the predominant pathology and 15% of patients were HER2-positive. The majority of patients had low neutrophils (< 75%) and high lymphocyte percentages (>15%), (82.9%, 77.8%, respectively). Noteworthy, about one third of patients had low serum albumin level at diagnosis (≤ 3 g/dl) (Table 1).

Table 1: Baseline characteristics of the study of study patients.

Parameters N (%)
Gender
Male 90 (66.7)
Female 45 (33.3)
Age
≤40 years 18 (13.3)
>40 years 117(86.7)
≤70 years 117(68.7)
>70 years 18(13.3)
Stage at initial Diagnosis
II-III 23 (17.0)
IV 112 (83.0)
Pathology
Adenocarcinoma 97 (71.8)
Others 38 (28.2)
Her2 status
Positive 21 (15.5)
Negative 79 (58.5)
Unknown 35 (26.0)
Site of Primary
GEJ and fundus 34(25.2)
Other 101(74.8)
Number of metastatic sites
Single 87(64.5)
Multiple 48(35.5)
Body mass index (BMI)
<25 87(64.5)
≥25 48(35.5)
≤ 30 118(87.4)
> 30 17(12.6)
First-line systemic therapy
Yes 111 (82.2)
No 24 (17.8)
Neutrophil count
≤ 7/mcL 110 (81.5)
>7 k/mcL 25 (18.5)
Neutrophil Percentage
≤ 75% 112 (82.9)
>75% 23 (17.1)
Lymph count
≤ 2.9 /mcL 109 (80.7)
> 2.9 /mcL 26 (19.3)
Lymph Percentage
≤ 15% 30 (22.2)
> 15% 105 (77.8)
Neutrophil / lymphocyte ratio
≤ 2.5 67 (49.6)
>2.5 68 (50.4)
Esinophil count of 0.4 k/mL
≤ 0.4 /mcL 102 (75.5)
>0.4 /mcL 33 (24.5)
Platelets
≤ 450 /mcL 115 (85.2)
>450K/mcL 20 (14.8)
Albumin
≤ 3 g/dL 47 (34.8)
> 3 g/dL 88 (65.2)
Chemotherapy regimen
FOLFOX/CAPEOX 30 (27.0)
EOF/EOX 31 (28.0)
Cisplatin and 5-FU 16 ( 14.4)
Taxane containg regimen 27 (24.3)
Others 7 (06.3)
Chemotherapy cycles number
<4 27 (24.4)
4-6 61 (54.9)
>6 23 (20.7)

After a median follow up of 21.4 months, the median OS and PFS were 11.0 and 6.1 months, respectively. Higher albumin level (> 3 g/dl) (8.1 vs 4.9 months, p=0.001), low neutrophil percentage ≤ 75% (6.9 vs. 2.7 months, p=<0.00001) (Figure 1A)=(Figure 1), high lymphocyte percentage > 15% (7.4 vs. 3 months, p=<0.00001) (Figure 2A)=(Figure 2), neutrophil/lymphocyte ≤ 2.5 (9.8 vs. 6.6 months, p=0.009), high eosinophil count >0.4 k/ml (8.9 vs. 5.5 months, p=0.001) (Figure 3A)=(Figure 3), and EOX/EOF chemotherapy vs. doublet chemotherapy (10.6 vs. 6.0 months, p=0.022 ) were associated with improved PFS in univariate analysis.

Figure 1: Progression free survival according to the percentage of neutrophils (cutoff 75%).

Figure 2: Progression free survival according to the percentage of lymphocytes (cutoff 15%).

Figure 3: Progression free survival according to eosinophil count.

However, BMI, pathological type, HER2 status, platelet count, basophil count, number of metastatic sites and number of chemotherapy cycles were not associated with PFS (Table 2).

Table 2: Progression Free Survival of study patients according to different parameters.

Parameters PFS HR (95% CI) p
Gender
Male 6.1 0.92 (0.60-1.41) 0.69
Female 5.9
Age
≤ 40 years 7.4 0.78 (0.41-1.47) 0.44
>40 years 5.7
≤ 70 years 6.2 0.87 (0.48-1.58) 0.66
>70 years 5.1
Stage at initial Diagnosis
II-III 4.1 0.61 (0.35-1.07) 0.08
IV 6.9
Pathology
Adenocarcinoma, NOS 5.8 0.90 (0.58-1.40) 0.64
Others 6.9
Her2 status
Positive 6.8 0.91 (0.16-1.81) 0.93
Negative 6.1
Site of Primary
GEJ and fundus 8.0 096 (0.59-1.53) 0.85
Other 5.6
Number of metastatic sites
Single 5.6 0.92 (0.61-1.39) 0.69
Multiple 7.4
Body mass index
<25 5.6 0.90 (0.59-1.38) 0.634
≥ 25 6.8
≤ 30 6.1 0.89 (0.48-1.64) 0.707
> 30 8.1
Neutrophil count
≤ 7 /mcL 5.7 0.95 (0.58-1.55) 0.83
>7 /mcL 7.8
Neutrophil Percentage
≤75% 6.9 0.32 (0.18-0.58) <0.00001
>75% 2.9
Lymph count
≤ 2.9 /mcL 5.7 0.79 (0.49-1.27) 0.32
> 2.9 /mcL 8.1
Lymph Percentage
≤ 15% 3.0 0.37 (021-0.64) <0.00001
> 15% 7.4
Neutrophil / lymphocyte ratio
≤ 2.5 7.4 0.59 (0.39-0.88) 0.009
>2.5 5.4
Esinophil count
≤ 0.4 /mcL 5.5 0.45 (0.27-0.73) 0.001
>0.4 /mcL 9.0
Platelet count
≤ 450 /mcL 6.2 0.59 (0.34-1.04)
>450 /mcL 5.8 0.066
Serum Albumin
≤ 3 g/dL 4.9 0.49 (0.32-0.75) 0.001
> 3 g/dL 8.1
Chemotherapy regimen
EOF/EOX 9.0
Others 4.3 0.28 (0.12-0.68) 0.022
Chemotherapy cycles number
≤6 6.1
>6 9.0 0.57 (0.31-1.05) 0.157

Noteworthy, in multivariate analysis, only serum albumin (HR=0.59, 95% CI=0.35-0.99, p=0.049) and eosinophil levels (HR=0.51, 95% CI= 0.29-0.78, p= 0.014) were significantly associated with PFS. However, neutrophil percentage did not reach statistical significance (HR= 1.9, 95% CI= 0.96-3.95, P=0.06).

Regarding OS, in univariate analysis, higher serum albumin (>3 g/dl) (14 vs. 5.6 months, p= <0.0001), low neutrophil percentage ≤ 75% (12.0 vs. 3.3 months, p=0.001) (Figure 1B)=(Figure 4) , high lymphocyte percentage > 15% (12.7 vs. 3.3 months, p=<0.0001) (Figure 2B)=(Figure 5), neutrophil/lymphocyte ≤ 2.5 (13.2 vs. 7.8 months, p=0.002), higher eosinophil count (14.2 vs. 8.9 months, p=0.002) (Figure 3B)=(Figure 6), receiving 1st line chemotherapy vs.

Figure 4: Overall survival according to the percentage of neutrophils (cutoff 75%).

Figure 5: Overall survival according to the percentage of lymphocytes (cutoff 15%).

Figure 6: Overall survival according to eosinophil count.

no chemotherapy (12.2 vs. 1.5 months, p=0.0000), receiving >6 cycles of chemotherapy (18 vs. 10.6 months, p=0.013) receiving EOX/EOF chemotherapy vs. doublet chemotherapy (17.2 vs. 12.2 months, p=0.004), platelet count ≤ 450 k/ml (12.0 vs. 8.1 months, p=0.049), male gender (13.2 vs. 8.1 months, p=0.017) were associated with improved OS (Table 3).

Table 3: Overall Survival of study patients according to different parameters.

Parameters OS HR (95% CI) p
Gender
Male 13.2 0.61 (0.40-0.92) 0.017
Female 8.1
Age
≤ 40 years 10.6 0.92 (0.49-1.73) 0.80
>40 years 11.0
0.71
≤ 70 years 11.0 1.12 (0.62-2.01)
>70 years 9.5
Stage at initial Diagnosis
II-III 5.3 0.50 (0.28-0.89) 0.016
IV 12.0
Pathology
Adenocarcinoma, NOS 9.5 0.85 (0.54-1.33) 0.47
Others 14.2
Her2 status
Positive 11.4 0.51 (0.27-0.98) 0.022
Negative 12.2
Site of Primary
GEJ and fundus 11.0 0.96 (0.61-1.52) 0.88
Other 11.8
Number of metastatic sites
Single 9.4 0.98 (0.65-1.49) 0.942
Multiple 12.7
Body mass index
<25 11.8 0.91 (0.59-1.39) 0.65
≥ 25 8.7
0.34
≤ 30 11.8 0.75 (0.42-1.35)
> 30 8.1
Neutrophil count
≤ 7 /mcL 10.7 0.94 (0.58-1.51) 0.79
>7 /mcL 17.4
Neutrophil Percentage
≤75% 12.0 0.43 (0.26-0.72) 0.001
>75% 3.3
Lymph count
≤ 2.9 /mcL 10.4 0.56 (0.33-0.94) 0.026
> 2.9 /mcL 17.4
Lymph Percentage
≤ 15% 3.3 0.30 (0.18-0.51) <0.00001
> 15% 12.7
Neutrophil / lymphocyte ratio
≤ 2.5 13.2 0.53 (0.35-0.81) 0.002
>2.5 7.8
Esinophil count
≤ 0.4 /mcL 8.9 0.66(0.49-0.88) 0.002
>0.4 /mcL 14.2
Esinophil percentage
≤6 % 11.0 0.87 (0.32-2.39) 0.79
>6% 9.1
Basophil count
≤ 0.1 k/mL 10.6 0.60 (0.29-1.25) 0.169
> 0.1 k/mL 21.0
Basophil Percentage
≤ 1% 10.6 0.68 (0.34-1.35) 0.261
> 1% 14.2
Platelet count
≤ 450 k/ml 12.0 0.57 (0.32-1.01) 0.049
>450K/ml 8.1
Serum Albumin
≤ 3 g/Dl 5.6 0.37 (0.24-0.57) <0.00001
> 3 g/dL 14.0
Chemotherapy regimen
EOF/EOX 17.2 0.40 (0.16-0.92) 0.004
Others 11.3
Chemotherapy cycles
≤ 6 10.6 0.58 (0.33-1.02) 0.013
>6 18.0

Noteworthy, in multivariate analysis, higher serum albumin (HR=0.35, 95% CI= 0.18-0.66, p=0.001) lower neutrophil percentage (HR=2.35, 95% CI= 1.01-4.99, p=0.49), male gender (HR=1.69, 95% CI= 1.01-2.82, p=0.046) and higher number of chemotherapy cycles (HR=0.56, 95% CI= 0.36-0.87, p=0.01) were independently associated with OS.

Discussion

Advanced stage GC has dismal prognosis with short survival outcome with limited therapeutic improvement in the last years compared to many other cancer types. Many factors have been proposed to predict the prognosis of various types of cancer, however, many of them are expensive or unreliable enough [3].

Tumour inflammatory reaction plays a crucial role in tumor microenvironment as the interaction between inflammatory cells, cytokines and tumour cells is critically involved in cell proliferation, angiogenesis, invasion, and metastasis [15][16][17][18][19][20][21].

However, it seems that the relation between inflammation and malignancy is rather complex and still not fully understood. Malignant cells can promote inflammatory response through the release of reactive oxygen species, nitric oxide and remodeling of the extracellular matrix [22]. Meanwhile, by the release of growth factors, cytokines, proangiogenic factors and proteolytic enzymes within the microenvironment, platelets and inflammatory cells can enhance tumor cell growth and invasion [23][24].

The peripheral blood count, routinely performed within the daily practice, can partly reflect the inflammatory response. Noteworthy, pretreatment assessment of blood counts eliminated the influence of systemic treatment, which yields more prognostic value of their assessment [25]. Several studies highlighted the prognostic role of various inflammation-based factors including the PLR, NLR, and platelet count in various types of solid tumors, such as breast cancer,[9] colorectal cancer,[26] esophageal squamous cell carcinoma,[27] liver cancer,[28] and small cell lung cancer [29].

Similarly, several studies also demonstrated the prognostic value of blood cells specially NLR, PLR, in GC [30][31][32]. Moreover, a meta-analysis including 10 studies with almost 3000 cases confirmed the poor survival outcome of elevated baseline NLR in gastric cancer [33]. In addition, baseline NLR before surgery showed prognostic value in patients with GC who underwent surgical resection in univariate but not multivariate analysis [32].

Furthermore, it was reported that NLR is a more powerful prognostic factor compared to PLR [25]. The lymphocyte response plays an important role in immune responses, and it is also a major factor in the suppression of cancer progression [34]. As NLR is the ratio of neutrophils to lymphocytes, high NLR means a relatively higher neutrophils and lower lymphocyte levels. Therefore, high NLR reflects an imbalance in the immune response to tumour cells [22].

Interestingly, in our study, higher NLR was linked with adverse survival outcome in univariate analyses but lost its value in multivariate analysis. In contrast, elevated neutrophil percentage at base line, a possible biomarker of inflammatory tumour response, was a powerful independent predictor of OS and of borderline significance in term of PFS. Elevated neutrophil percentage may then reflect a more aggressive tumour biology and clinical behavior. Moreover, higher eosinophil count was associated with improved PFS. Normally, eosinophils are involved in inflammatory response to bacterial and parasite infection in addition to allergic reactions. Recent studies highlighted the role of eosinophils in lymphocyte recruitment and activity in allergic reaction [35]. However, the role of eosinophils in tumour immune response is still to be elucidated. Moreover, our finding needs to be validated in a larger cohort of patients to highlight the exact prognostic value of baseline eosinophils in GC.

Our study reinforced the prognostic value of baseline serum albumin which was displayed and well established by several earlier studies. Therefore, according to our results, simple assessment of basline serum albumin and neutrophil percentage could provide a valuable prognostic tool for advanced gastric cancer patients. Finally, our study has some limitations including the retrospective nature and the relatively small patients’ cohort. However, we have the advantage of joint assessment of different components of blood cells, laboratory, clinicopathological and therapeutic parameters. This highlighted the powerful prognostic value of baseline blood cells levels even after adjusting for other competing prognostic variables.

In conclusion, easily measured parameters such as serum albumin and neutrophil percentage were associated with important prognostic value with background biological relevance linked to nutritional status of the patient and inflammatory response to the tumour, reflecting tumour aggressiveness, respectively. These parameters should be taken in consideration while choosing first line systemic therapy and even in stratifying patients recruited in clinical trials.

Acknowledgements

-This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

-The authors declare no conflict of interest.

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Copyright

© Asian Pacific Journal of Cancer Care , 2020

Author Details

Shereef Elsamany
Oncology Center, King Abdullah Medical City, Oncology Center, Mansoura University, Mansoura, Egypt
shereefmohamad@yahoo.com

Ahmed Zeeneldin
Oncology Center, King Abdullah Medical City, Saudi Arabia, National Cancer Institute, Cairo Universirt, Cairo, Egypt

Emad Tashkandi
Oncology Center, King Abdullah Medical City, Saudi Arabia

Ayman Rasmy
Oncology, Zagazig University, Zagazig, Egypt, Oncology, King Soud Medical City, Riyadh, Saudi Arabia

Waleed Abozeed
Clinical Oncology, Mansoura University, Mansoura, Egypt

Gomaa Abdelfatah
Oncology Center, King Abdullah Medical City, Makkah Saudi Arabia, Clinical Oncology, Faculty of Medicine, Bani Suef University, Egypt

Huda Bukhari
Research, Um Alqura University, Makkha, Saudi Arabia

Mernan Sulaimani
Research, Um Alqura University, Makkha, Saudi Arabia

Donia Firaq
Research, Um Alqura University, Makkha, Saudi Arabia

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