Correlation of preoperative anemia subtypes with tumor characteristics, systemic inflammation and immediate postoperative outcomes in gastrointestinal cancer patients – a prospective observational study

doi:10.21203/rs.3.rs-2132365/v1

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Research Article

Correlation of preoperative anemia subtypes with tumor characteristics, systemic inflammation and immediate postoperative outcomes in gastrointestinal cancer patients – a prospective observational study

https://doi.org/10.21203/rs.3.rs-2132365/v1

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Journal Publication

published 12 Jan, 2023

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Purpose

Patients with Gastrointestinal (GI) malignancies more frequently present with anemia. A large proportion of them exhibits a systemic inflammatory response causing anemia of chronic disease. Although tumor factors play an essential role in determining the prognosis, studies have also reported the role of host factors in the outcome. This study was done to determine the association between systemic inflammation, tumor characteristics, and immediate postoperative outcome among various anemia subgroups.

Methods

This was a single-center, prospective observational study of patients undergoing treatment for GI cancers. The modified Glasgow prognostic Score (mGPS) was calculated and patients were followed up until discharge regarding postoperative complications, length of the hospital, ICU stay, and mortality. The patient demographics, tumor characteristics, systemic inflammation, and postoperative complications were studied among different subtypes of anemia.

Results

A total of 209 patients were analysed, and a higher prevalence of normocytic anemia (52.63%) and systemic inflammatory response (62.21%) was observed among the study population. Systemic inflammation was significantly associated with a higher nodal stage (p = 0.02) and margin positivity (p = 0.006). Patients with higher mGPS had significantly higher requirements for blood transfusion (p = 0.003), superficial SSI (p = 0.03), and sepsis (p = 0.02), however, other postoperative complications were comparable among patients without an inflammatory response.

Conclusion

High prevalence of systemic inflammation and resultant normocytic anemia among GI cancers warrants thorough knowledge in this field among the treating surgeons. This study opens up a platform for further research to consider anti-inflammatory agents in its management to circumvent the morbidity of blood transfusions.

Gastrointestinal (GI) malignancies represent more than one-quarter (26%) of the global incidence of cancers and also account for more than one-third (35%) of deaths related to cancers. About 4.8 million new cases of gastrointestinal (GI) cancers and 3.4 million related deaths, were reported worldwide, in 2018.[1] The current burden of these cancers warrant the need for future planning to prioritize and implement early treatment actions without much delay. Patients with GI malignancies frequently have anemia at the time of diagnosis, and at times it is this anemia, which brings the patient to the health care facilities. Anemia in GI cancers is multifactorial, causes include malnutrition and/ or malabsorption leading to nutritional deficiencies, acute or chronic hemorrhage, systemic inflammation, bone marrow suppression which may be therapy-induced or by direct tumor metastasis and a decline in the endogenous erythropoietin or reduced sensitivity to the same. A large proportion of the patients with GI cancers present with a systemic inflammatory response which leads to anemia of chronic disease.[2] There is reduced iron uptake and absorption secondary to the release of inflammatory cytokines which is characterized by increased serum levels of C-reactive protein (CRP) and decreased serum albumin levels.[3] The combination of these two parameters forms the essential element of the modified Glasgow Prognostic Score (mGPS). Similar to tumor factors, it is increasingly recognized that host factors also have a prognostic role.[4] In particular, the presence of an innate systemic inflammatory response before surgery is associated with poorer survival across a wide variety of tumours.

Though the treatment of anemia in cancer patients improves their quality of life and has better treatment tolerability, thus improving the prognosis, [5] it is also associated with adverse events such as major, and minor incompatibility reactions, higher rates of postoperative infective complication and disease recurrence.[6] Furthermore, iron replacement therapy can be more harmful to a patient’s systemic inflammatory response against the tumor, as the side effects may outweigh the beneficial effects. Anemia has been identified as an independent predictor of poor prognosis among cancer patients.[7] However, the prognostic significance of anemia in relation to several other potentially confounding prognostic parameters which include, systemic inflammation, tumor characteristics, and immediate postoperative outcomes in different anemia subgroups have not been studied. Thus, this study was carried out to predict the association of pre-operative anemia subgroups with systemic inflammation, tumor characteristics, and immediate post-operative outcome in gastrointestinal cancer patients undergoing treatment.

Study Design:

This was a single-centre, prospective, observational study conducted in the Department of Surgery in a tertiary care centre. This study was approved by the Institute Research Monitoring Committee and Institute Ethics Committee (JIP/IEC/2019/94). All consecutive patients above 18 years of age who have undergone elective gastrointestinal cancer surgery were included in the study after obtaining informed consent. Patients with existing inflammatory and hematological disorders, active infections, active bleeding, renal insufficiency, any history of blood transfusion and iron supplements in the preceding 12 weeks, and patients undergoing emergency surgeries were excluded from the study.

This trial was registered under Clinical Trial Registry of India with trial no: CTRI/2020/07/026773.

Sample size calculation:

The sample size was calculated using OpenEpi version 3.01 assuming the prevalence of systemic inflammation (mGPS > 0) among anaemic patients undergoing treatment for GI cancers as 26%, relative precision of 20% and confidence level of 95%. The final sample size was calculated to be 206. [2]

Study procedure:

After obtaining an informed consent from the patients the details such as age, sex, body mass index (BMI), American nsociety of anesthesiologist (ASA) grade, symptom duration, other relevant clinical history, past history including co-morbid conditions, nature of work, history of smoking and alcoholism, blood investigations such as complete blood count, liver function test, relevant imaging results, presence or absence of distant metastasis, intra operative and post-operative complications, perioperative blood transfusion, characteristics of the tumor such as tumor size, position, differentiation, Tumor staging, Nodal staging, high- risk tumour features, like poor differentiation, presence of lymo-vascular, perineural invasion, peritoneal involvement and margin involvement were identified from pathology reports. In addition, length of hospital stay, and in hospital mortality were collected.

A 10 ml venous blood sample was collected before initiating any treatment and the hemoglobin levels, mean corpuscular volume (MCV), CRP, and albumin levels were measured. From this data, mGPS was calculated. CRP < 10 mg/dl, with any levels of serum albumin was given a score 0, CRP > 10mg/dl with albumin > 35g/l was given a score of 1, and CRP > 10mg/dl with an albumin < 35g/l was given a score of 2. Anemia was defined according to WHO guidelines, haemoglobin (Hb) < 130 g/L for males and Hb < 120 g/L for females.[8] Anaemia was further classified as microcytic anaemia with MCV < 80 f/L, normocytic anaemia with MCV 80–100 f/L, and macrocytic anaemia with MCV > 100 f/L. The superficial surgical site infection, deep surgical site infection, intra-abdomen infection, wound infection, urinary tract infection, catheter-related infection, and pneumonia, sepsis were diagnosed and recorded, according to the Centers for Disease Control and Prevention (CDC) classification.[9]

Data collection and outcome variables:

The independent variables like demographic details, clinical history, past history including comorbid conditions, personal history including smoking, tobacco and alcoholism, family history of malignancies, ASA grade, blood investigations such as blood sugar, LFT, hemoglobin levels, MCV, serum iron, ferritin, transferrin saturation, findings of relevant imaging, type of surgical procedure, surgical approach (laparoscopy/ laparotomy) were collected. The outcome variables such as serum albumin levels, CRP, postoperative morbidity and in-hospital mortality were also recorded. The primary outcome was to study the effect of systemic inflammation on tumor characteristics and immediate postoperative outcome among various anemia subgroups in patients who underwent treatment for GI cancers. The secondary outcome was to study the association of tumor characteristics and immediate post-operative outcome among different grades of modified Glasgow prognostic score (systemic inflammation) in patients who underwent treatment for GI cancers as well as to assess the difference if any in the prevalence of anemia and severity of inflammatory response in the upper GI and lower GI cancers.

Statistical analysis:

Continuous variables were tested using student t-test and Mann-Whitney test accordingly. Categorical data were tested using Chi-square test. Univariate analysis was carried out to identify the risk factors for postoperative complications. Further, multivariate analysis was carried out for variables with p value of < 0.10 in the univariate analysis to identify the independent risk factors for postoperative complications. All statistical analysis was done using SPSS version 19 and a P value of less than 0.05 was considered to indicate statistical significance.

A total of 209 consecutive patients of gastrointestinal malignancy with anemia were included in this study, of which 99 (47.36%) patients had microcytic anemia, 110(52.63%) patients had normocytic anemia, while there were no patients with macrocytic anemia. 79 (37.79%) patients had a mGPS of 0, 50 (23.92%) had mGPS 1, 80 (38.27%) had mGPS 2.

The overall mean age was 54.39 ± 11.77 years. The mean age of patients, male to female ratio, and BMI were comparable between the microcytic and normocytic group. Also the presence of comorbidities, high-risk behaviour, and ASA grade among the two anemia groups were comparable (p = 0.37, p = 0.46, p = 0.83). (Table-1)

The tumor characteristics including the location of the tumor, histopathology, the TNM (Tumor, Node, Metastasis) stage, lymphovascular invasion, perineural invasion, margin status, and surgical intent were studied and found to be comparable among the two anemia groups. On the contrary, on comparing the systemic inflammation among the two anemia groups using the modified Glasgow Prognostic Score (mGPS), patients with normocytic anemia had a significantly higher systemic inflammation than patients with microcytic anemia (p = 0.01). (Table-2)

On assessing the postoperative complications and comparing them among the patients with microcytic and normocytic anemia, although there was an increased hospital and ICU stay among the patients with normocytic anemia, this difference was not statistically significant (p = 0.324 for hospital stay and p = 0.393 for ICU stay). The occurrence of infectious complications such as superficial, deep surgical site infection, organ space infection, sepsis, pneumonia, and urinary tract infection (UTI) were comparable between the two anemia subgroups. The non-infective complications such as acute kidney injury, cardiac complications, anastomotic leak and mortality were also similar among the anemia subgroups, except for postoperative ileus, which was significantly high in the normocytic anemia group (p = 0.02). It was also found that the patients with microcytic anemia had a significantly higher requirement for perioperative blood transfusion. (p = < 0.001) (Table-3)

On comparing the tumor characteristics with mGPS score, it was found that the tumor location, histopathology, T-stage, tumor metastasis, lymphovascular invasion, perineural invasion, and surgical intent were not significant, however, the higher nodal stage and positive margins were significantly associated with higher systemic inflammation (p = 0.020; p = 0.006). (Table-4) Similarly, on comparing the postoperative complications with mGPS score, it was found that the infective complications such as superficial SSI, and sepsis were significantly associated with higher mGPS score (p = 0.03; p = 0.02). Other infective complications such as deep SSI, organ space infection, pneumonia, and UTI were not significantly associated with systemic inflammation. It was noted that a higher number of patients with blood transfusion was significantly associated with a higher mGPS score (p = 0.003). On comparing the Clavien Dindo score with mGPS score, it was found that there were significantly higher grades of complications among patients with higher systemic inflammation (p = 0.01). (Table-4)

In comparing anemia subtypes with the upper and lower gastrointestinal tract malignancies, both microcytic and normocytic anemia were equally distributed. (p = 0.987). On the contrary, there was a significant difference between the upper and lower GI tract in terms of systemic inflammation (p = 0.043). A comparison of postoperative complications with the location of the tumor showed significantly higher rates of superficial SSI, deep SSI, organ space, and UTI among lower GI malignancies (p < 0.001, p = 0.001, p = 0.001, p = 0.007). On the contrary, higher rates of pneumonia were noted among patients with upper GI malignancies (p = 0.001). The need for blood transfusion was significantly higher among patients with upper GI malignancies (p = 0.013). The other parameters such as sepsis, acute kidney injury,, ileus, anastomotic leak, and mortality were similar between the groups. (Table-5)

Univariate analysis of the patient factors and tumor factors was carried out to find the independent risk factors for complications. It was found that the higher BMI (p = 0.015), normocytic anemia (p = 0.046), and the presence of comorbidity (p = 0.022) were significantly associated with higher complication rates. Similarly, among the tumor factors, higher T stage (p < 0.001), moderately & poorly differentiated tumor (p = 0.045), lower GI malignancies (p < 0.001), non-metastatic disease (p < 0.001), curative surgery (p < 0.001) were significantly associated with postoperative complications (Table-6). On performing a multivariate logistic regression analysis on the parameters which were significant in univariate analysis, it was found that lower GI malignancies (OR: 2.30; p = 0.036), Tumor stage 3 (OR: 4.86; p < 0.001), normocytic anemia (OR: 2.05; p = 0.031), and the presence of comorbidities (OR: 2.48; p = 0.002) were independent factors associated with a higher postoperative complication.

Anemia has a massive burden in managing gastrointestinal malignancies. The pathogenesis of anemia in GI cancer is multifactorial, and even in a single patient, different mechanisms act at different points of time.[9] Studies have shown anemia as an independent predictor of poor prognosis among cancer patients. In a systemic review of 60 studies that evaluated the overall survival, it was found that there was a 65% overall increase in the risk of mortality in patients with anemia.[7] This could be explained by delay or failure to initiate definitive management in anemia patients. There is a decrease in oxygen transport in anemia, which facilitates intra-tumoral hypoxia and thus, activation of Hypoxia-Inducible Factors (HIF), which are the key regulators of disease progression.[10] Treatment of anemia in cancer improves the quality of life and has better treatment tolerability, thus improving the prognosis.[5, 11] It is believed that microcytic anemia forms a significant contributor in patients with GI malignancies. Not many studies consider systemic inflammation and the resultant anemia of chronic disease in GI cancers. This remains a grey area in the management of GI malignancies. This study aimed to find the association between systemic inflammation, tumor characteristics, and immediate postoperative outcome among various anemia subgroups in patients who undergo treatment for all GI cancers.

Our study included 209 patients with GI malignancies. We found a relatively higher number of patients with normocytic anemia (52.6%) compared to microcytic anemia (47.3%). We found that microcytic anemia was associated with younger age, lower BMI, and a significantly lower systemic inflammation assessed by mGPS score compared with normocytic anemia. Both the anemia groups were comparable in terms of other patient demographics, and tumor characteristics. The microcytic group required a significantly higher rate of blood transfusion than the other. However, both the anemia subgroups had a similar pattern of postoperative complications, while there were relatively higher rates in the normocytic group. On analysing the systemic inflammation, we found that patients with systemic inflammation had a higher age at presentation, higher BMI, higher nodal stage, higher-margin positivity, and longer duration of hospital and ICU stay rates than patients without inflammation. Patients with higher mGPS scores had significantly higher requirements for blood transfusion. In comparing the postoperative complications too, these patients had higher rates of both infective and noninfective complications. On further analysis to study the diversity of upper and lower GI cancers, we found that the lower GI cancers had a significantly higher rate of postoperative wound-related and urinary complications. In contrast, the upper GI cancers had significantly higher blood transfusions and pneumonia rates. On multivariate logistic regression, the presence of comorbidities, higher T stage, normocytic anemia, and lower GI cancers were found to be independent risk factors for postoperative complications.

Both the anemia groups were comparable in the essential demographic characteristics. The mean age of the study population was 54.39 + 11.77 years. We have a relatively younger population of cancer patients. In both the subtypes of anemia, there was a higher male to female ratio among all the study groups, which could be due to higher tobacco and alcoholism among males. There was an equal number of normocytic anemia in all malignancies just similar to colonic malignancies. This finding disagrees with the well-known fact that microcytic anemia is a commoner in colorectal malignancy.[11] In a study conducted by Väyrynen JP et al., the average MCV was lower with a higher T stage, suggesting the prevalence of iron deficiency in such higher stages.[2] On the contrary, in the present study, we noted an equal representation of the anemia types across all the stages. A study of 872 colorectal cancer patients reported, the association of systemic inflammation among patients with normocytic anemia.[12] Similarly, in the present study, patients with normocytic anemia had a higher mGPS score and a higher systemic inflammation. On further analysis of the study participants based on grades of systemic inflammation, we found that the relative age was higher in patients with systemic inflammation. In a large multicentre Korean study reported by Kim et al., the incidence of systemic complications was significantly increased in patients over 60 years old similar to the present study.[13]

It was noted that the patients with inflammatory responses against tumors had a higher requirement for blood transfusions. This is because there is excessive production of hepcidin (a regulatory protein that controls iron absorption) from the liver under the influence of cytokine release seen in systemic inflammation, which reduces the iron absorption from the gut and also reduces the release of iron from the stores into the bloodstream. Thus, these patients will be non-responders to conventional iron therapy. Thus, they continue to have low hemoglobin despite iron supplementation necessitating blood transfusion, subjecting them to the risks of the same and a potential delay in definitive management.[14]

In a study conducted in Japan higher preoperative mGPS scores had worse outcomes and survival rates, in patients with gastric cancer.[15] Another study conducted in United Kingdom reported a poor overall and cancer-specific survival following resection of the colorectal cancer among patients with high mGPS score.[16] similarly In the present study, it was noted that higher the systemic inflammatory response higher was the stage of the disease in terms of nodal, and metastatic burden and Lymphovascular, and perineural invasion also in both infective and non infective complications. Thus, it is prudent to say that patients with systemic inflammation had an aggressive tumor and had a poor postoperative recovery. On further analysis, we found that lower GI malignancies had significantly higher rates of SSI, and sepsis. In a study by Silvestre et al., the rate of postoperative infective complications following elective colorectal surgery was also high (42%) which was comparable to our study where we had 54.9%.[17] In a retrospective study including 516 patients of esophagectomy states that there was high rate of pulmonary infection (38%).[18] Similarly, in the present study, upper GI patients had higher rates of pulmonary complications, need for blood transfusions, anastomotic leak, and ultimately mortality. The possible reason for the high rate of postoperative pulmonary infection could be that we have included patients with metastatic disease undergoing palliative bypass surgery and patients belonging to lower socioeconomic status who had poor nutritional status making them prone to develop pulmonary complications.

In our study, we observed that the higher the tumor stage, higher was the postoperative complications. This is because the higher stage of the disease evokes a much higher immune response and thus higher systemic inflammation compared to the early stages. In a study conducted in United Kingdom they found that an increasing magnitude of innate systemic inflammation was associated with poorer cancer-specific survival.[12]

In our study we found that age and sex do not affect the post-operative complications significantly, which was similar to few other published studies in the literature.[19, 20] Considering the tumor location, lower GI surgeries had a higher odds of postoperative complications. Combined mechanical bowel preparation with luminal antibiotics can help circumvent these complications.[21] Higher the tumor stage, the higher the odds of complication. This stresses the importance of aggressive screening approaches to detect these malignancies at an earlier stage, thereby ensuring a complete and curative surgery rather than a morbid or palliative surgery in these patients.

Finally, patients with normocytic anemia had significantly higher rates of complications than microcytic anemia, as anemia by itself is an independent outcome predictor. Peri-treatment optimization of hemoglobin levels will ensure improved clinical outcomes. Here arises the question of blood transfusion in anemia management. Although blood transfusion is helpful to combat anemia, evidence is proving poor clinical outcomes with blood transfusion.[22] Amato A et al found that perioperative blood transfusions showed detrimental effects on recurrence among patients undergoing curative surgery in colorectal cancers.[6] The exact mechanism of these is still under scrutiny. Transfusion-related immunomodulation or pro-inflammatory changes may contribute to activated tumor status.[23] Also, the knowledge of anemia of chronic disease and its prevalence among GI cancers is still lacking. Reports have shown poor outcomes and survival among these subgroups of anemia. This could be due to the delay in definitive management owing to the refractory anemia resistant to our conventional management. Apart from this, these populations have been subjected to a higher burden of blood transfusions, which trigger a further inflammatory response. This study opens up the scope for further research in the use of anti-inflammatory agents to tackle this inflammatory response which can ensure an earlier and better optimization without the morbidity of blood transfusion and early institution of definitive management.

In the present study, there was a high prevalence of normocytic anemia among patients with GI malignancies which had a higher systemic inflammation than the microcytic group. The normocytic group had relatively higher rates of postoperative complications and a higher burden of blood transfusions. We emphasize that there is a higher prevalence of systemic inflammation and resultant normocytic anemia among GI cancers. Treating them with conventional anemia measures may not be fruitful as this may delay initiating definitive management. Also, the burden and morbidity of blood transfusion imposed on them are substantially high. A thorough knowledge of this field among the treating surgeons will be more beneficial to the patients. This study opens up a platform for further research to consider anti-inflammatory agents in managing this crisis to circumvent the morbidity of blood transfusions.

Funding:

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Competing interests:

The authors have no relevant financial or non-financial interests to disclose.

Author contribution:

Sudharshan Mahalingam has Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work;

Karthikrajan parasuraman udayakumar has Drafted the work and revised it critically for important intellectual content;

Sureshkumar Sathasivam has approved the final version to be published;

Anandhi Amaranathan is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Availability of data and materials:

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Ethics approval:

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Institutional Ethics Committee of Jawaharlal Institute of Postgraduate Medical Education and Research (Date 28/08/2019/ No: JIP/IEC/2019/94)

Consent to participate:

Informed consent was obtained from all individual participants included in the study

Grant support:

Nil

Conflict of interest:

None declared

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Table-1: Comparison of demographic details of patients with microcytic and normocytic anemia

Factor	Total N=209 Mean (SD)	Microcytic anemia n=99 Mean (SD)	Normocytic anemia n=110 Mean (SD)		p-value*
Age(years)	54.39 (11.77)	55.35 (11.11)	53.35 (12.33)		0.27*
Gender					0.08^#
Male	131 (62.68)	56 (42.75)	75 (57.25)
Female	78 (37.32)	43 (55.13)	35 (44.87)
BMI	17.98+2.57	17.88+2.35	18.08+2.76	0.58*
Comorbidity None Hypertension Diabetes Both Others^&	111(53.11) 67(32.05) 56(26.79) 34(16.27) 14(6.69)	49(49.49) 35(35.35) 28(28.28) 20(20.20) 8(8.08)	62(56.36) 32(29.09) 27(24.54) 14(12.73) 6(5.44)	0.37^#
Risk factors No Smoking Alcoholism Both	46 (22.01) 120 (57.42) 115 (55.02) 104 (49.75)	24(24.24) 54 (54.55) 53 (53.54) 49 (49.49)	22 (20.00) 66 (60.00) 62 (56.36) 55 (50.00)	0.46^# 0.43^# 0.68^# 0.94^#
ASA Grade				0.83^#
I	12 (5.74)	6 (6.06)	6 (5.45)
II	192 (91.87)	90 (90.91)	102 (92.73)
III	5 (2.39)	3 (3.03)	2 (1.82)

*Independent student t-test, # chi square test; &- CKD- Chronic Kidney Disease, CLD- Chronic Liver Disease, CAD- Coronary Arterial Disease, , ASA- American Society of Anaesthesiology.

Table-2: Comparison of tumor characteristics and systemic inflammation among patients among anemia subtypes

Factor	Total N=209 (%)	Microcytic anemia n=99 (%)	Normocytic anemia n=110 (%)	p-value*
Tumour location^$				0.383
Esophagus	31(14.83)	10(10.10)	21(19.09)
Stomach	69(22.01)	37(37.32)	32(29.09)
Colon	62(29.29)	30(30.30)	32(29.09)
Rectum	44(21.05)	21(21.21)	23(20.91)
GE Jn	3(1.44)	2(2.02)	1(0.91)
Histopathology				0.43
Well differentiated	111(53.11)	53(53.53)	58(52.73)
Moderately differentiated	44(21.05)	19(19.19)	25(22.73)
Poorly differentiated	40(19.14)	22(22.22)	18(16.36)
Others^&	14(6.28)	5(5.05)	9(8.18)
T Stage				0.82
T1	5(2.40)	2(2.04)	3(2.73)
T2	24(12.02)	13(13.27)	12(10.91)
T3	70(33.65)	36(36.73)	34(30.91)
T4	19(9.13)	8(8.16)	11(10.00)
Complete pathological response	1 (0.48)	0 (0.00)	1 (0.91)
Nodal status				0.88
N0	51(24.4)	27(27.27)	24(21.82)
N1	29(13.88)	12(12.12)	17(15.45)
N2	30(14.35)	14(14.14)	16(14.55)
N3	14(6.7)	7(7.07)	7(6.36)
Metastasis	53(25.36)	26(26.06)	27(24.55)	0.95
Lymphovascular Invasion	63(30.14)	27(27.27)	36(32.73)	0.36
Perineural invasion	26(12.44)	8(8.08)	18(16.36)	0.14
Margin positivity	9(4.31)	2(2.02)	7(6.36)
Surgical intent				0.87
Curative	130(62.20)	61(61.62)	69(62.73)
Palliative	79(37.80)	38(38.38)	41(37.27)
mGPS				0.01
mGPS 0	79(37.98)	45(45.92)	34(30.91)
mGPS 1	50(24.04)	15(15.31)	35(31.82)
mGPS 2	80(37.98)	39(39.3)	41(37.27)

*Chi square test; mGPS- modified Glasgow Prognostic Score; &-Mixed Adeno Neuro Endocrine Carcinoma (MANEC), High grade dysplasia, Leiomyosarcoma, Gastro Intestinal Stromal Tumor (GIST) , Adenomatous Polyp, Non-Hodgkin’s Lymphoma (NHL).

Table-3: Comparison of postoperative complications among patients with microcytic and normocytic anemia

Total

N=209

(%)

Microcytic anemia n=99

(%)

Normocytic anemia n=110

(%)

p-value*

Superficial Surgical Site Infection

Deep surgical site infection

Organ space infection

Sepsis

Pneumonia

Acute kidney injury

Urinary tract infection

Ileus

Anastomotic leak

Blood transfusion

Others

Mortality

122(58.37)

34(16.27)

49(23.44)

24(11.48)

26(12.44)

22(10.53)

23(11.00)

6(2.87)

1(0.48)

46(22.01)

6(2.8)

3(1.44)

55(55.56)

16(16.16)

27(27.07)

12(12.12)

10(10.0)

9(9.1)

0(0.00)

37(37.37)

3(3.03)

2(2.02)

67(60.91)

18(16.36)

22(20.0)

12(10.91)

16(14.55)

13(11.82)

14(12.73)

6(5.45)

1(0.91)

9(8.19)

3(2.7)

1(0.91)

0.43

0.97

0.22

0.78

0.33

0.52

0.40

0.02

1.00

<0.001

0.42

0.60

Postoperative hospital stay

10 (8.215)

10.16(8.81)

11.29(7.64)

0.32^#

Days of ICU stay

Ventilator support

Inotrope support

1.37 (1.85)

20(9.57)

10(4.7)

1.26 (1.90)

9(9.09)

5(5.05)

1.47 (1.81)

11(10.0)

5(4.8)

0.39^#

0.82^*

0.57^*

*Chi square test; #- Mann-Whitney test; Others- Upper Gastrointestinal bleed, stoma related complication, re-exploration, closed loop obstruction, infected pleural effusion.

Table-4: Relationship between mGPS and tumor characteristics, postoperative complications,

	Total N=209 (%)	mGPS 0 n=79 (%)	mGPS 1 n=50 (%)	mGPS 2 n=80 (%)	p value
Tumor Histopathology					0.22*
Well differentiated	110(52.88)	41(51.90)	34(68.0)	35(44.30)
Moderately differentiated	44(21.15)	20(25.32)	7(14.0)	17(21.52)
Poorly differentiated	40(19.23)	15(18.99)	6(12.0)	19(24.05)
Others^&	15(7.17)	3(3.8)	3(6.0)	9(11.25)
T Stage					0.19*
T1 T2	5(2.42) 25(12.08)	1(1.27) 14(17.72)	3(6.0) 6(12.0)	1(1.28) 5(6.41)
T3	70(33.77)	27(34.18)	18(36.0)	25(31.25)
T4	19(9.18)	6(7.59)	4(8.0)	9(11.54)
Nodal status					0.02*
N0	51(24.04)	20(25.32)	15(30.0)	16(20.0)
N1	29(13.94)	10(12.66)	13(26.0)	6(7.59)
N2	30(14.42)	15(18.99)	5(10.0)	10(12.66)
N3	14(6.73)	3(3.80)	2(4.0)	9(11.39)
Metastatic disease	53(25.48)	20(25.32)	8(16.00)	25(31.65)	0.37*
Lymphovascular Invasion	63(30.29)	25(39.68)	17(26.98)	21(33.33)	0.39
Perineural invasion	26(12.50)	9(34.62)	6(23.08)	11(42.31)	0.13*
Margin positive	9(4.33)	2(22.22)	0(0.00)	7(77.78)	0.006*
Surgical intent					0.22*
Curative	130(62.22)	48(60.76)	36(72.0)	46(57.5)
Palliative	79(37.98)	31(39.24)	14(28.0)	34(43.04)
Superficial SSI	121(58.17)	44(55.70)	37(74.0)	40(50.63)	0.03*
Deep SSI	34(16.35)	8(10.13)	9(18)	17(21.5)	0.14*
Organ space infection	48(23.08)	15(18.9)	11(22.0)	22(27.8)	0.41*
Sepsis	24(11.54)	7(8.86)	2(4.0)	15(18.9)	0.02*
Pneumonia	26(12.50)	9(11.39)	3(6.0)	14(17.72)	0.14*
AKI	22(10.58)	7(8.86)	5(10.0)	10(12.66)	0.73*
UTI	22(10.58)	6(7.59)	7(14.0)	9(11.39)	0.49*
Blood transfusion	46(22.12)	18(22.78)	3(6.00)	25(31.65)	0.003*
Mortality	3(1.44)	2(2.53)	0(0.00)	1(1.27)	0.79*
Post-operative hospital stay	10(8.21)	9.91(5.70)	10.44(6.44)	11.78 (10.90)	0.79^#
Days of ICU stay	1.37(1.85)	1.32(1.77)	1.16(1.07)	1.54(2.29)	0.91^#
Clavien Dindo
0	56(26.92)	25(31.65)	12(24.0)	19(23.75)	0.01*
1	41(19.71)	19(24.0)	13(26.0)	9(11.25)
2	61(29.33)	23(29.1)	14(28.0)	24(30.00)
3	15(7.17)	0(0.00)	7(14.0)	8(10.0)
4	33(15.87)	10(12.6)	4(8.0)	19(23.75)
5	3(1.44)	1(1.25)	0(0.00)	2(2.53)

*Chi square test; # Mann-Whitney test $-Tumour location mentioned denotes the primary area of tumour location irrespective of its extension; &-Mixed Adeno Neuro Endocrine Carcinoma (MANEC), High grade dysplasia, Leiomyosarcoma, Gastro-Intestinal Stromal Tumor (GIST) , Adenomatous Polyp, Non-Hodgkin’s Lymphoma (NHL); GE- gastro esophageal; mGPS- modified Glasgow Prognostic Score.

Table-5: Comparison of anemia subtypes, mGPS, post-operative complications with upper and lower GI malignancies

Factors

Total

N=209

(%)

Upper GI

n=102

(%)

Lower GI

n=107

(%)

p-value*

Anemia subtypes

Microcytic

Normocytic

mGPS

99(47.13)

110(52.88)

79(37.77)

50(24.15)

80(38.27)

48(47.06)

54(52.94)

41(40.20)

17(16.67)

44(43.17)

51(47.87)

56(52.83)

38(35.51)

33(31.43)

35(32.71)

0.987

0.043

Superficial SSI

Deep SSI

Organ space

Sepsis

Pneumonia

Acute kidney injury

UTI

Ileus

Anastomotic leak

Blood transfusion

Mortality

122(58.65)

34(16.35)

49(23.56)

24(11.54)

26(12.50)

22(10.58)

23(11.06)

6(2.88)

1(0.48)

46(22.12)

3(1.44)

43(42.16)

8(7.84)

14(13.73)

15(14.71)

21(20.59)

8(7.84)

5(4.90)

1(0.98)

30(29.41)

3(2.94)

79(74.53)

26(24.53)

25(33.02)

9(8.49)

5(4.72)

14(13.21)

18(16.98)

1(0.94)

0(0.00)

16(15.09)

0(0.0)

<0.001

0.001

0.161

0.001

0.209

0.007

0.088

0.307

0.013

0.075

*;chi square test; GI: Gastrointestinal; mGPS- modified Glasgow Prognostic Score.

Table-6: Univariate analysis of patient factors and tumor factors associated with major postoperative complications

Factors	No complications N=70 (%) Or Mean(SD)	Complications N=139 (%) Or Mean(SD)	p-value*
Age, years	54.84+12.81	54.17+11.26	0.697^*
Sex			0.141
Male	39(29.77)	92(70.23)
Female	31(39.74)	47(60.26)
BMI	17.36+1.89	18.30+2.80	0.015^*
Hypoalbuminemia	24(30.00)	56(70.00)	0.400
Anemia
Microcytic Normocytic mGPS 0 1 2	40(40.40) 30(27.27) 30(37.97) 11(22.00) 29(36.71)	59(59.60) 80(72.73) 49(62.03) 39(78.00) 51(63.29)	0.046 0.133
ASA			0.445
I	4(33.33)	8(66.67)
II	63(32.81)	129(67.19)
III	3(60.00)	2(40.00)
Comorbidity	25(25.51)	73(74.49)	0.022
T stage			<0.001
T1	0(0.00)	5(100.00)
T2	9(36.00)	16(62.00)
T3	13(18.57)	57(81.43)
T4	0(0.00)	19(100.00)
Histopathology			0.045
Well differentiated Moderately differentiated Poorly differentiated Others^$ Tumour location Upper GI Lower GI Metastasis	13(18.06) 1(5.26) 9(28.13) 1(25.00) 46(45.10) 23(21.70) 30(56.60)	59(81.94) 18(94.74) 23(71.88) 3(75.00) 46(54.90) 83(78.30) 23(43.40)	<0.001 <0.001
Type of resection Curative Palliative	26(20.00) 44(62.86)	104(80.00) 35(44.30)	<0.001

*-Independent student t-test; Chi-square test; BMI- Body Mass Index; ASA- American Society of Anaesthesiology;

mGPS- modified Glasgow Prognostic Score; $; MANEC-Mixed Adeno Neuro Endocrine Carcinoma (MANEC), High grade dysplasia, Leiomyosarcoma, GIST-Gastro Intestinal Stromal Tumor (GIST) , Adenomatous Polyp, NHL-Non-Hodgkin Lymphoma (NHL);GI- Gastrointestinal.

No competing interests reported.

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Correlation of preoperative anemia subtypes with tumor characteristics, systemic inflammation and immediate postoperative outcomes in gastrointestinal cancer patients – a prospective observational study

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