INTRODUCTION
Upper urinary tract carcinoma (UTUC) is a malig- nant tumor of the urothelium of the urinary tract from calyx to distal ureter.1 UTUC is relatively uncommon, and represents only 5%-7% of the tumors that develop in the kidneys.1 UTUC accounts for approximately 5%-10% of all genitourinary malignancies.1 The disease has a multifocal nature and is diagnosed twice as often in the renal pelvis, as in the ureters.2 The standard treatment for localized UTUC is a radical nephroureterectomy (RNU), with bladder cuff excision.3 RNU series studies performed in the last years have shown that the proportion of locally advanced UTUC is about 60%, the proportion of high-grade tumors is about 70%, and that the proportion of aggressive disease is increasing.4 The 5-year survival rate of UTUC is 20%, and the prognosis is relatively poor.5 For these advanced UTUCs, adjuvant chemo- therapy (ACH) is recommended to improve long- term prognosis.6 However, some advanced UTUC patients progress or the disease recurs to a distant metastasis site.7 About 7% of patients experience metastatic disease.8 It is important to accurately predict oncologic outcomes and to properly classify patients at risk for progression or recurrence, to perform additional salvage treatments. For this reason, prognostic factors of survival before treatment are clinically important. We have focused on alanine aminotransferase (ALT) and aspartate aminotransferase (AST), among the many pretreatment predictive factors. ALT and AST are liver enzymes commonly used in different clinical fields, and have been reported in several studies as important biomarkers in various malignant tumors, such as kidney cancer, lung cancer, pan- creatic cancer, and colorectal cancer, as well in as chronic liver disease.9-12 Recent studies have also shown that UTUC was useful as a preoperative predictor.13-15 However, no studies have been reported on the role of AST and ALT as prognostic factors in patients with end-stage UTUC, who received ACH. Therefore, we aimed to identify the prognostic significance of AST and ALT before ACH, in patients with UTUC who underwent RNU and ACH.
MATERIALS AND METHODS
1. Ethics Statement
The study was approved by the Institutional Review Board of Seoul National University Hospital (IRB No. 2018-11-018). We conducted a retrospective case study and were exempted from obtaining prior consent of the patients. The research protocol was in accordance with the Declaration of Helsinki guidelines.
2. Study Sample
We retrospectively analyzed the medical records of 204 patients with advanced UTUC. (pathologic T3 or T4 or pathologic T1- T2N1-N3 without distant metastasis) who were treated in 2 institutions from January 2000 to December 2017. These patients underwent RNU after being diagnosed with UTUC, followed by first line ACH after diagnosis with advanced-stage disease. Of 204 patients, 16 patients suspected of fatty liver and chronic liver disease, and 8 patients suspected of systemic infection and inflammation, were excluded, and 4 patients with incomplete data were also excluded. A total of 176 patients were included in the analyses.
3. Study Design
We divided the patients into 2 groups, according to the optimal value of the AST/ALT ratio. The optimal AST/ALT ratio was determined to have the highest sensitivity and specificity in the receiver operating characteristic curve. Patients were divided into 2 groups based on an optimal AST/ALT of 1.2.
ACH usually started within 3 months after surgery, depending on the general condition and renal function of the patients. Laboratory tests including AST and ALT were routinely performed the day before the first cycle of ACH.
The clinical and pathological data collected on patients for this study were: patient age, body mass index (BMI), sex; underlying diseases, such as hypertension and diabetes; RNU surgery methods; pathologic T stage and N stage; tumor grade, presence of lymphovascular invasion, presence of concurrent carcinoma in situ, presence of ipsilateral hydronephrosis, presence of multifocality, presence of positive surgical margin, regimen and cycle of ACH, American Society of Anesthesiologists (ASA) physical status classification before ACH, and AST and ALT before ACH. Oncologic outcomes data were also collected for mortality, and mortality due to cancer.
Histopathological evaluation of surgical specimens was examined by pathologists skilled in the genital area. The TNM stage and tumor grade were assessed using the 2010 American Joint Committee on Cancer Tumor, Node, Metastases classification, and the World Health Organization/International Society of Urological Pathology consensus classi- fication.
Follow-up was performed every 3 months for the first 2 years, then every 6 months for 2 to 5 years, and every 1 year thereafter. Physical examination, routine laboratory tests, urine analysis, urine cytology, and cystoscopy were performed at every follow-up. Chest computed tomography (CT), abdominal pelvic CT were performed routinely every year.
4. Statistical Analysis
Clinical and pathological characteristics were analyzed by independent t-tests between groups. The continuous variables were expressed as mean, standard deviation, median and interquartile range, and the nominal variables were expressed as probability through crossover analysis. The oncologic outcome was analyzed by Kaplan- Meier survival analysis and log-rank test. Several pretreatment factors affecting the oncologic outcome were analyzed by multivariate Cox pro- portional hazard regression analysis. A total of 82 patients with high AST/ALT ratios were matched in a 1:1 ratio to 94 patients with low AST/ALT ratios using the nearest neighbor method with 0.02 calibrated. Propensity matching was performed to compensate for the difference between age, sex, BMI, ASA, Tumor location, operative type. The propensity score matching was calibrated and differentiated in most items with a standardized mean difference of less than 0.05. All statistical tests were performed using IBM SPSS Statistics ver. 22.0 (IBM Co., Armonk, NY, USA), and a p-value of <0.05 was considered to indicate statistical significance.
RESULTS
The clinicopathologic characteristics of all patients are shown in Table 1. Patients were divided into 2 groups based on an AST/ALT ratio of 1.2. Mean age was 61.4 years and mean AST/ALT ratio was 1.2. Overall mortality was 47.7%, cancer-specific mortality was 44.3%, and mean survival time was 50.5 months. Twenty-eight percent of patients experienced recurrence within the bladder during follow-up. In the high AST/ALT group, the mean age was 64.1 years (p=0.015), the mean mortality rate was 65.9% and the cancer-specific mortality rate was 61.0% (p=0.003 and p=0.006), higher than the low AST/ALT group. The mean survival time of the high AST/ALT group was 40.4 months (p=0.020), which was shorter than the low AST/ALT group. Overall survival (OS) was poor in the high AST/ALT group compared to the low AST/ALT group (p=0.007), and the cancer-specific survival was also poor in the high AST/ALT group, compared to the low AST/ALT group (p=0.011) (Fig. 1).
Fig. 1.
Overall and cancer-specific survival analyses. Kaplan-Meier survival curves comparing overall and cancer-specific survivals according to the aspartate aminotransferase/alanine aminotransferase (AST/ALT).
Table 1.
Clinicopathological characteristics of patients before and after propensity score matching
In multivariate analysis, age (hazard ratio [HR], 1.041; 95% confidence interval [CI], 1.003-1.074; p=0.039), pT3 or higher (HR, 1.464; 95% CI, 1.156-1.857; p=0.002), LVI (HR, 1.445; 95% CI, 1.153-1.854; p=0.005), pN1-N2 (HR, 1.342; 95% CI, 1.011-1.773), pN3 (HR, 3.893; 95% CI, 2.284-6.648; p<0.001), high AST/ALT ratio (HR, 5.428; 95% CI, 1.803-16.334; p=0.002), were significant predictors of poor OS. And pT3 or higher (HR, 1.475; 95% CI, 1.172-1.904; p=0.002), pN3 (HR, 3.815; 95% CI, 2.235-6.493; p<0.001), high AST/ALT ratio (HR, 4.417; 95% CI, 1.545-12.632; p=0.005) were significant predictors of poor cancer-specific sur- vival (CSS) (Table 2).
Table 2.
Multivariate Cox proportional hazards analyses of the AST/ALT ratio on overall survival and cancer-specific survival
After propensity score matching, the overall mortality rate was significantly higher (65.9% vs. 34.1%) in the high AST/ALT group (p=0.008) and the cancer-specific mortality rate were also significantly higher (61.0% vs. 31.7%) in the high AST/ALT group (p=0.015) than in the low AST/ALT group (Table 1). The multivariate Cox analysis showed that a high prechemotherapy AST/ALT ratio was a significant independent predictor of poor prognosis such as OS (HR, 2.095; 95% CI, 1.090-4.024; p=0.026), CSS (HR, 2.074; 95% CI, 1.053-4.086; p=0.035) (Table 3). In addition, pathologic T stage, N stage, positive surgical margin are also associated with poor prognosis (Table 3).
Table 3.
Multivariate Cox proportional hazards analyses of the AST/ALT ratio on overall survival and cancer-specific survival after propensity score matching
DISCUSSION
In this study, we evaluated patients with increa- sed AST/ALT. We observed poor survival outcomes after ACH for advanced UTUC. The AST/ALT ratio was a predictor of OS (HR, 5.428; 95% CI, 1.803-16.334; p=0.002) and CSS (HR, 4.417; 95% CI, 1.545-12.632; p=0.005). Previous studies on UTUC have also reported that the AST/ALT ratio is a predictor of oncological prognosis.13-15 Lee et al.14 reported that preoperative high AST/ALT ratio was significantly associated with a poor prognosis of progression-free survival (PFS), CSS, and OS (all p<0.001) in 263 UTUC patient who underwent RNU. They also reported that a high preoperative AST/ALT ratio greater than 1.5 was an independent predictor of PFS (HR, 2.335; 95% CI, 1.633-3.340; p=0.001), CSS (HR, 2.550; 1.689-3.851; p=0.001), and OS (HR, 2.069; 95% CI, 1.409-3.038; p<0.001) through Cox multivariate analysis.14 Cho et al.13 reported that a high preoperative AST/ALT ratio was significantly associated with a poor prognosis of CSS and OS (all p=0.001), in a multicenter study of 1,049 patients who underwent RNU. They also reported that a preoperative AST/ALT ratio higher than 1.6 was an independent predictor of CSS (HR, 2.49; 95% CI, 1.70-3.64; p=0.001) and OS (HR, 1.84; 95% CI, 1.34-2.52; p=0.001) through Cox multivariate analysis.13 In Nishikawa's study of 109 patients with localized UTUC who underwent RNU, a high AST/ALT was significantly independent of extravesical recurrence-free survival (HR, 4.21; 95% CI, 1.95-9.08; p<0.001). In a study of 153 patients with urothelial bladder cancer who underwent radical cystectomy, Gorgel et al.16 reported that the preoperative AST/ALT ratio was significantly associated with a poor prognosis of disease- specific survival (DSS) and OS (all p<0.001). They also reported that preoperative AST/ALT ratios higher than 1.3 were independent predictors of DSS (HR, 5.79; 95% CI, 2.25-15.13; p<0.001) and OS (HR, 2.61; 95% CI, 1.49-4.56; p<0.001) through Cox multivariate analysis.16
The exact mechanism of the relationship between elevated AST/ALT and poor prognosis of cancer patients, including those with UTUC is not yet known. But there are several hypotheses that explain the relationship between AST/ALT ratio and cancer. The most prominent of them is the Warburg effect.17 In normal cells, energy is produced by mitochondrial oxidative phosphorylation. However, cancer cells produce energy through lactic acid fermentation glycolysis, rather than oxidative phosphorylation, even under oxygen- rich conditions. This aerobic glycolysis is a less efficient pathway than oxidative phosphorylation, and increases the production of metabolites that can contribute to cancer cell proliferation. These metabolites provides anabolic support essential for cancer cell proliferation and growth.17 Increased lactate has been suggested to play an important role in maintaining glycolysis, affecting lactate dehydrogenase, the Nicotinamide adenine dinucleotide (NADH)/Nicotinamide adenine dinucleotide (NAD)+ratio, and affecting glucose transport materials. AST plays an important role in the process by relocating NADH to the mitochondria.18,19 In addition, increases in glucose metabolites due to increased lactate, affects the microenvironment of the tumor and promotes local invasion, progression, and metastasis of cancer cells.18,19
This study has some limitations. First, since this was a retrospective study of a relatively small number of patients, there may be a recall bias. However, the study population was limited to UTUC patients who underwent RNU and ACH, and that limited the number of patients. Second, we didn't know whether the patient was taking unchecked drugs that would affect AST/ALT.
Despite the limitations, this is the first study to identify the AST/ALT ratio as an important prognostic biomarker of ACH in advanced UTUC. There are many cancer biomarkers, but the AST/ALT ratio has the merit of cost effectiveness, com- pared with other methods, and the advantage that it is a quick method that may predict prognosis before cancer treatment.
CONCLUSIONS
An increased AST/ALT ratio is a significant inde- pendent predictor of CSS and OS in advanced UTUC patients receiving systemic ACH after RNU. We suggest that the AST/ALT ratio is a useful and valuable biomarker for predicting oncological outcomes after systemic ACH, as well as RNU in UTUC. The results presented here provide an important insight into the clinical significance of aminotransferase-based markers in postoperative UTUC patients with progressive stage disease, receiving ACH.
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