Predictive value of the FIB-4 index, APRI, ALBI score, and GPR for overall survival in treatment-naïve metastatic colorectal cancer patients

doi:10.21203/rs.3.rs-5289132/v1

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Predictive value of the FIB-4 index, APRI, ALBI score, and GPR for overall survival in treatment-naïve metastatic colorectal cancer patients

https://doi.org/10.21203/rs.3.rs-5289132/v1

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Background:

The prevalence of metastatic colorectal cancer (mCRC) is increasing and is linked to poor overall survival (OS). Previous studies have aimed to determine the predictive value of scores and laboratory tests for OS in mCRC patients, but their findings have been inconclusive. In this research, we focused on determining the prognostic significance of the fibrosis-4 (FIB-4) index, the aspartate aminotransferase (AST) to platelet (PLT) ratio index (APRI), the albumin–bilirubin (ALBI) score, and the gamma-glutamyl transpeptidase to PLT ratio (GPR) with respect to OS in treatment-naïve mCRC patients.

Methods:

This retrospective study included treatment-naïve mCRC patients. The FIB-4 index, ALBI score, APRI, and GPR were calculated for each participant, and their mortality dates were recorded. The clinical importance of these scores for survival outcomes was evaluated via the Cox regression model, Kaplan–Meier method, and log-rank test.

Results:

The study enrolled 123 untreated mCRC patients. Univariate Cox regression analysis demonstrated that sex and AST/PLT and ALT/PLT counts were not associated with OS (p>0.05 for all). However, a higher FIB-4 index (p=0.025), ALBI score (p<0.001), GPR (p<0.001), and AST/ALT ratio (p<0.001) were all associated with poor OS. Additionally, multivariate Cox regression analysis indicated that age (95% CI: 1.009–1.053, p=0.006), ALBI score (95% CI: 1.234–2.983, p=0.004), GPR (95% CI: 1.442–2.701, p<0.001), and AST/ALT (95% CI: 1.193–2.911, p = 0.006) were independent prognostic factors for OS.

Conclusion:

The affordable and easily accessible ALBI score, GPR, and AST/ ALT have prognostic value in untreated patients with mCRC.

Colorectal neoplasms

Survival

Predictive value of tests

Organ dysfunction scores

In recent years, the prevalence of colorectal cancer (CRC) has significantly increased among both men and women and is leading to cancer-related fatalities.¹ Approximately 20% of individuals diagnosed with CRC have metastatic disease at their time of diagnosis.² In addition to the liver, regional lymph nodes, the lungs, and the peritoneum could be listed as the most prevalent metastasis sites for CRC.² The liver, the leading site for distant organ metastasis in CRC patients, determines patient survival time.³ Although surgical resection can provide a 5-year survival rate for approximately two-thirds of patients, only 10–20% of those with CRC with liver metastases are eligible for surgery.²

The main goal in treating metastatic CRC (mCRC) is to provide patient with an optimal quality of life for the longest possible time.³ Therefore, clinicians should consider factors such as tumor stage and size, underlying liver functions, and the patient performance status. In recent years, increasing interest has been in determining predictive biomarkers for numerous cancers via serologic and hematologic tests ⁴. A decline in liver function among CRC patients affects the prognosis of the disease.⁵ The albumin–bilirubin (ALBI) score indicates the severity of liver dysfunction.^4,6 The aspartate aminotransferase (AST)-to-platelet (PLT) ratio index (APRI), the fibrosis-4 (FIB-4) index and the gamma-glutamyl transpeptidase (GGT)-to-PLT ratio (GPR) are significantly associated with liver fibrosis.^7–9

This retrospective study focused on determining the prognostic significance of scores and markers derived from biochemical tests and hemogram parameters such as the FIB-4 index, ALBI score, APRI, and GPR, on OS in CRC patients with liver metastasis who had not previously received any systemic chemotherapy or local ablative therapy or who had undergone surgery, as detected during the staging process via [18F]fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (¹⁸FDG-PET/CT) imaging.

This retrospective study enrolled newly diagnosed CRC patients with liver metastases confirmed via ¹⁸FDG PET/CT; these patients had no distant metastases other than those in the liver or lymph nodes, had not undergone surgery, and had not received any systemic chemotherapy or local ablative therapy, and received at least one course of chemotherapy after imaging between 01/01/2017 and 01/05/2023. Twenty-seven patients whose data were unavailable or who had additional malignancies were excluded.

Age, sex, and biochemical liver tests and hemogram parameters were retrieved for each patient. The ALBI score, FIB-4 index, and APRI were determined via the following formulas: (I) ALBI score = (log₁₀ bilirubin (µmol/L) × 0.66) + (albumin (g/L) × −0.0852), (II) FIB-4 index = (age (years) x AST (U/L)) / (PLT (10⁹/L]) x (ALT (U/L)^1/2), and (III) APRI = [(AST level (IU/L)/ AST (upper limit of normal) (IU/L) /PLT count (109/L)] × 100.^6,8,10 Furthermore, the GPR, a fibrosis-related parameter, and the inflammatory parameters AST/PLT, ALT/PLT, and AST/ALT ratios were calculated from biochemical liver tests and hemogram data.⁹ The dates of death of the patients were noted.

The local ethics committee granted approval for the study protocol (approval date and number: 2024 − 111). Because the study was retrospective, participants were not asked to provide written informed consent when enrolled. All procedures were conducted according to the Good Clinical Practices Guidelines set by the Turkish Medicine and Medical Devices Agency and the Declaration of Helsinki.

Statistical analysis was performed via SPSS (IBM Corporation, Armonk, New York, United States) version 26.0. The Kaplan–Meier test (product limit method) and log-rank analysis were used to investigate the impacts of factors on mortality and survival. To measure the effects of prognostic variables on mortality and survival, univariate and multivariate Cox regression analyses were performed via the Enter method. Quantitative variables are expressed as the mean ± standard deviation and median (25th/75th percentile), whereas categorical variables are expressed as n (%). Variables were analyzed at the 95% confidence level, and p < 0.05 was considered statistically significant.

One hundred twenty-three patients with mCRC who had not received prior treatment were included. The median age was 59 (17–92) years, and 56.1% (n = 69) of the participants were male. No statistically significant difference was observed in terms of sex between survivors and nonsurvivors (p > 0.05). The overall mortality rate was 85.4% (n = 105), and the median OS was 20.1 (min-max: 1-104) months (Table 1). Table 1 presents the participants' age, baseline scores, and laboratory findings.

Table 1

Age, baseline scores and laboratory findings of the participants.
	Alive			Exitus			Total
	N	Median	Min-Max	N	Median	Min-Max	N	Median	Min-Max
Age	18	50.50	23.0–79.00	105	59.00	17.0–92.00	123	59.00	17.0–92.00
Albumin	15	3.70	2.70–4.6	93	3.80	1.80–4.8	108	3.80	1.80–4.80
Total Bilirubin	16	0.37	0.170–2.3	100	0.58	0.100–17.6	116	0.57	0.100–17.60
ALBI score	14	-2.61	-3.60- -1.24	89	-2.57	-3.50- -0.07	103	-2.57	-3.60- -0.07
AST	18	23.00	7.0–87.00	105	23.00	10.0-2135.00	123	23.00	7.0-2135.0
ALT	18	26.00	8.0–77.00	105	17.00	6.0-1129.00	123	17.00	6.0-1129.0
ALP	7	92.00	66.0-573.00	62	122.00	43.0-672.00	69	122.00	43.0-672.0
GGT	10	20.00	13.0-344.00	68	53.50	10.0-1475.00	78	49.00	10.0-1475.0
PLT	18	288.50	177.0-693.00	105	282.00	88.0-667.00	123	282.00	88.0-693.0
INR	11	1.26	1.16–1.47	70	1.18	0.99–1.98	81	1.19	0.99–1.98
FIB-4 Index	18	1.04	0.11–2.27	105	1.25	0.25–26.18	123	1.22	0.11–26.18
AST to PLT	18	0.11	0.01–0.30	105	0.09	0.02–4.44	123	0.09	0.01–4.44
ALT to PLT	18	0.09	0.01–0.30	105	0.07	0.01–2.35	123	0.07	0.01–2.35
GGT to PLT	10	0.09	0.02–1.17	68	0.23	0.02–4.79	78	0.21	0.02–4.79
AST to PLT	18	1.11	0.48–2.09	105	1.38	0.51–4.15	123	1.32	0.48–4.15
ARPI	18	0.31	0.03–0.85	105	0.26	0.06–12.68	123	0.26	0.03–12.68
OS	18	56.13	4-97.40	105	18.23	1-103.63	123	20.17	1-104
N: Number; Min: Minimum; Max: Maximum; ALBI score: Albumin–bilirubin score; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; ALP: Alkaline phosphatase; GGT: Gamma-glutamyl transpeptidase; PLT: Platelet; INR: International normalized Ratio; FIB-4: Fibrosis-4 index; APRI: AST to platelet ratio index; OS: Overall survival

Univariate Cox regression analysis revealed that sex, AST/PLT, and ALT/PLT were not significantly associated with OS (p > 0.05 for all). On the other hand, the FIB-4 index (p = 0.025), ALBI score (p < 0.001), GPR (p < 0.001), and AST/ALT ratio (p < 0.001) were associated with poor OS (Table 2).

The multivariate Cox regression analysis demonstrated that age (95% CI: 1.009–1.053, p = 0.006), ALBI score (95% CI: 1.234–2.983, p = 0.004), AST/ALT (95% CI: 1.193–2.911, p = 0.006), and GPR (95% CI: 1.442–2.701, p < 0.001) were independent prognostic factors for OS, as summarized in Table 2.

Table 2

Univariate and multivariate Cox regression analyses.
	Univariate analysis					Multivariate analysis
	B	OR	95% CI		p	B	OR	95% CI		p
			Lower	Upper				Lower	Upper
Age	0.012	1.012	0.999	1.026	0.080	0.030	1.031	1.009	1.053	0.006
ALBI score	0.767	2.153	1.556	2.977	0.000	0.652	1.919	1.234	2.983	0.004
FIB-4 Index	0.063	1.065	1.008	1.125	0.025	-0.022	0.979	0.901	1.063	0.607
AST to PLT	0.287	1.332	0.918	1.932	0.131
ALT to PLT	0.363	1.437	0.639	3.234	0.381
GGT to PLT	0.572	1.772	1.343	2.339	0.000	0.680	1.973	1.442	2.701	0.000
AST to ALT	0.574	1.775	1.371	2.299	0.000	0.623	1.864	1.193	2.911	0.006
APRI	0.100	1.106	0.971	1.259	0.131
Gender	0.086	1.090	0.739	1.607	0.664
CI: Confidence interval; OR: Odds ratio; ALBI score: Albumin–bilirubin score; FIB-4: Fibrosis-4 index; PLT: Platelet; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; GGT: Gamma-glutamyl transpeptidase; APRI: AST to platelet ratio index; OS: Overall survival

The results of this study revealed that age, the ALBI score, the AST/ALT ratio, and the GPR are independent prognostic factors for OS among untreated de novo mCRC patients.

The objectives of treating mCRC are to increase patient quality of life for as long as possible and improve survival. Seth et al. reported that patients with CRC and liver metastases who underwent resection had a 5-year survival rate of approximately 35%.³ The outcome for individuals who underwent liver resection can be predicted before the surgery. The ALBI score is useful for objectively evaluating liver function.⁶ A decrease in the albumin level indicates liver synthesis dysfunction, leading to a decrease in the ALBI score.⁶

The ALBI score was first employed in patients with a diagnosis of hepatocellular carcinoma (HCC), and it has been noted as a cost-effective, straightforward, and impartial approach to evaluating liver function and as a predictive element in individuals with primary biliary cirrhosis or HCC.^6,9,11 Several subsequent studies have suggested that the ALBI score serves as a prognostic indicator for individuals diagnosed with breast, gastric, or pancreatic cancer.^12–14 A study by Koh et al. on stage 1–3 CRC patients revealed that the ALBI score was associated with progression-free survival via both univariate and multivariate analyses.¹⁵ Additionally, high ALBI scores and age are linked to disease-free survival and OS.¹⁵ In a different study, two randomized trials involving patients with stage 4 CRC were combined, and the ALBI score and age were found to be independent prognostic factors.¹⁶ In our study, we found that the ALBI score was linked to survival when patients were examined individually. When we conducted a multivariate analysis, we discovered that age and ALBI score independently influenced overall survival, suggesting that our findings aligned with prior research.

Regardless of its etiology, in chronic liver diseases, parenchymal injury progresses through a dynamic process that involves ongoing activation of the inflammatory response, continuous activation of liver fibrogenesis, and a wound healing response marked by the excessive buildup of extracellular matrix components by hepatic myofibroblasts.¹⁷ After initial reports on the importance of liver fibrosis in various types of hepatitis, several studies on mCRC patients reported that those with high liver fibrosis scores had a higher prevalence of liver metastases and recurrence than those with low liver fibrosis scores did.^8,18 Lemoine and colleagues proposed that the GPR provides more precise results than the APRI and FIB-4 index for detecting liver fibrosis in individuals with chronic hepatitis B.¹⁹ The combination of liver function and coagulation status is objectively reflected by the GPR.²⁰ There is increasing evidence that the GPR independently predicts the outcome of different types of cancer.^20,21 Ma et al. conducted a meta-analysis involving 1,952 patients and reported that the GPR has favorable accuracy, sensitivity, and prognostic value in patients with HCC.²² Nevertheless, we found no studies on CRC in the literature. Both univariate and multivariate analyses in the current study revealed that the GPR was an independent prognostic factor for predicting OS.

The degree of hepatocellular damage is associated with increased serum levels of ALT and AST. ²³ The ratio of AST to ALT is a biomarker that indicates liver function impairment and can be measured noninvasively. It has been utilized to evaluate the progression of fibrosis in liver diseases including nonalcoholic fatty liver disease (NAFLD).²³ The AST-to-ALT ratio has recently been demonstrated to act as a prognostic indicator for different types of cancer in recent times.^24,25 A study involving CRC patients revealed that higher AST levels and age were correlated with survival.²⁶

Moreover, in a study enrolling 536 stage 2–3 CRC patients, Scheipner et al. reported a potential decline in OS associated with a higher AST/ALT ratio. ²⁷ However, univariate and multivariate analyses did not indicate a statistically significant correlation.²⁷ In the present study, which included stage 4 CRC patients, the ratio of AST to ALT was determined to be a standalone prognostic indicator for OS via both univariate and multivariate analyses (p < 0.001, and p = 0.006, respectively).

The FIB-4 index, another noninvasive and inexpensive method for evaluating the extent of fibrosis in the liver, has been used in individuals with long-term liver disease, particularly hepatitis C virus.^7,10 NAFLD might be linked to increased liver metastasis. Studies using the FIB-4 index as an indicator of steatosis severity and evaluating the mechanisms associated with metastasis in CRC patients with NAFLD are limited. Patients with CRC may experience a decrease in simultaneous liver metastasis when they have advanced fibrosis in the liver due to NAFLD.²⁸

The frequency of NAFLD is rapidly increasing on a global scale; therefore, it is crucial for subsequent clinical studies involving CRC patients to focus on the incidence of NAFLD in different populations. To our knowledge, the effect of the FIB-4 index on prognosis in mCRC patients has not been studied. In the present study, we found that the FIB-4 index was a prognostic factor for OS in mCRC patients via univariate Cox regression analysis. Nevertheless, after multivariate analysis, the FIB-4 index did not stand as an independent prognostic factor for OS. The APRI is another index of hepatic fibrosis derived from AST and PLT measurements.⁸

In a multicenter study conducted with 1323 patients with CRC and liver metastases, the authors suggested that patients with a higher APRI had significantly better progression-free survival and OS than those with a lower APRI did (p < 0.05).²⁹ Ashouri et al. reported that among 2374 patients, the APRI was more effective in predicting postoperative liver failure than the Model for End-stage Liver Disease score was.³⁰ Additionally, the study indicated that an APRI value exceeding 0.365 independently served as a prognostic factor for posthepatectomy liver failure.³⁰ Even though the current study had a different design and patient selection, the univariate analysis did not show a notable distinction between the APRI and OS (p = 0.131) in stage 4 CRC patients.

The primary limitation of the current study its retrospective and single-center design. Another limitation is that subgroup analysis could not be performed as molecular subtypes were not analyzed. In addition, a statistical cutoff value could not be obtained for any parameter because most patients in our study died.

The main objective in managing mCRC involves maximizing the patient's quality of life for as much time as possible and increasing survival. In the present study, the ALBI score, GPR, AST/ALT ratio, and age were found to be independent prognostic markers for OS in CRC patients with liver metastases. These simple and affordable parameters may help clinicians predict disease prognosis and tailor treatment accordingly.

Ethics approval and consent to participate:

Consent for publication:

All authors give unconditional approval for the article to be published in the journal.

Competing interests:

The authors declare no competing interests.

Funding:

The authors declare no funding interests.

Author Contribution

M.S.Y, Y.G. ,H.K.AND B.B.B wrote the main manuscript text and C.C AND İ.K. prepared figures 1-2. All authors reviewed the manuscript.

Acknowledgements:

Nothing to declare.

Data Availability

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

Conflicts of interest:

There are no conflict of interest

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You are reading this latest preprint version

Predictive value of the FIB-4 index, APRI, ALBI score, and GPR for overall survival in treatment-naïve metastatic colorectal cancer patients

Status:

Version 1

Abstract

BACKGROUND

METHODS

RESULTS

DISCUSSION

CONCLUSIONS

Declarations

Ethics approval and consent to participate:

Consent for publication:

Competing interests:

Funding:

Author Contribution

Acknowledgements:

Data Availability

Conflicts of interest:

References

Additional Declarations

Status:

Version 1