Prognostic Analysis on Different Tumor Sizes for 14634 Hepatocellular Carcinoma Patients

Aim . Tis study investigated the efect of tumor size and other factors on the survival and prognosis of hepatocellular carcinoma (HCC). Methods . All HCC populations based on the National Cancer Institute’s SEER database to receive from 2010 to 2016 were employed in the study. Results . Tis study enrolled a total of 14,634 HCC. Among them, 1,686 patients had tumors ≤ 2 cm, 6,169 patients had tumors 2–5 cm, and 6,779 patients had tumors > 5 cm. Te results using univariate analysis showed that all factors were signifcant prognostic factors for overall survival and specifc survival. Patients with tumor size ≤ 2 cm were more likely to survive, while patients with tumor size > 5 cm had a lower survival rate. Patients who had surgery or surgery plus chemotherapy had a higher chance of survival in stages I-II, and the survival rate declined smoothly during the 80 months. Te change rate of the mortality rate increased rapidly during the period of 1–12 cm; afterwards, the mortality rate’s HR was basically and smoothly maintained at a high level. Conclusions . Tumor size was positively correlated with the mortality rate of HCC. Survival rates were greater in patients with tumors ≤ 2 cm who underwent surgery or surgery plus chemotherapy. Patients with HCC in the early stage had a higher survival probability particularly when they had experienced surgery or surgery plus chemotherapy.


Introduction
Hepatocellular carcinoma (HCC) with an extremely high mortality rate is one of the most common malignant tumors. Previous study [1] showed the HCC has the poor of prognosis, and its survival rate of 5-year was under 20%. HCC has a special feature: growth with metastasis to distant organs, which accounts for poor survival. Te HCC with distant metastasis is commonly found in the lungs, bones, and brain [2]. Moreover, the most common risk factor for HCC globally is the hepatitis B virus. In a previous study, the most common causative agent was the hepatitis C virus [3]. More than 90% of primary liver cancers are HCC [4]. In recent years, relevant research studies confrmed that specifc therapeutic regimens, including surgical resection, chemotherapy, and radiotherapy, provided HCC patients favorable prognosis and long-term survival. Te current meta-analysis from Francesca's study [5] found that regorafenib was a safe and efective treatment option for patients with advanced HCC. In addition, the efcacy and safety of microwave ablation and radiofrequency ablation were similar, but microwave ablation reduced the long-term recurrence rate [6]. A review summarized the trajectory of various aspects of HCC management over the last 15 years, providing additional information for clinicians to aggregate [7]. Previous research studies [8] found that HCC patients were more likely to feel hopeless, depressed, and even have serious suicidal thoughts. HCC monitoring for national minority and individuals of lower socioeconomic status was poorly performed, further exacerbating the diference in HCC prognosis among these disadvantaged populations [9]. Current therapeutic regimens, including surgery of liver resection, transplantation, radiotherapy, percutaneous ethanol injection, transarterial chemoembolization, microwave ablation, radiofrequency ablation, cryoablation, irreversible electroporation, combination therapies (such as postoperative adjuvant chemoradiotherapy and nutrition supportive therapy) and palliative care, will create high costs for HCC [10].
Te hepatic artery gives of the proper hepatic artery, and the portal vein repeatedly branches into the interlobular artery and interlobular vein after passing through the hepatic portal into the liver, which then branch into the hepatic lobule and drain into the blood sinus. Te proper hepatic artery and portal vein contribute to the metabolism of liver substances and regeneration of liver tissues, and they also provide abundant blood supply for the growth of liver tumors [11]. Larger liver tumors are prone to vascular infltration and nodules, and the possibility of advanced HCC and tumor proliferation is also increased, which directly afects the prognosis of patients with HCC [12]. At present, liver resection and liver transplantation are relatively feasible methods in the surgical treatment. Te prognosis of surgical treatment is related to tumor size, which may serve as an alternative marker of vascular infltration. Relevant researchers have shown that clinicians should be concerned about the HCC patients with tumor size ≥ 5.8 cm [2]. However, another study [13] showed that HCC > 50 mm have a high degree of vascular infltration which was associated with a poor prognosis. Tis study will further investigate tumor size and other factors on survival and prognosis of HCC.

Data Source.
All data of population-based cancer registries for this study were from the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) database, and all data were extracted by SEER * Stat (Version 8.3.8).

Population Selection and Classifcation.
Tis study selected patients who were diagnosed with HCC between 2010 and 2016. Te exclusion criteria in this study were as follows: (1) unknown of race; (2) unknown of survival time; (3) unknown of T, N, or M stage; (4) unknown of follow-up; (5) diagnosis at autopsy. We enrolled 14,634 patients who were assigned in groups with tumors ≤ 2 cm, tumors between 2 and 5 cm, and tumors greater than 5 cm. Age were divided in 0-50, 51-60, 61-70, and 70 + four. Te AJCC stage was also included, and the histological classifcation of liver cancer was performed. Patients diagnosed with HCC were grouped under the HCCspecial survival if the cause of death was also HCC. HCCspecial survival was calculated as the time from diagnosis to death from HCC.

Statistical
Analysis. Te Kaplan-Meier method and logrank testing were employed for evaluating overall all-cause HCC survival and HCC-special survival. Diferent tumor sizes and intervention regimens were discussed as important prognostic survival factors. Regression analysis was employed to estimate the relationship between hepatocyte tumor size and overall survival (OS). Univariate and multivariate Cox proportional risk models were used to assess the probability of death. Te hazard ratio (HR) was used as the statistical efect size. All statistical analyses were performed using R software (Version 4.0.0, R Foundation).

Baseline Characteristics.
In our study, 14,634 HCC patients were eligible and information is given in Table 1. Te number of patients with tumor size ≤ 2 cm was 1,686, patients with tumor size 2-5 cm accounted for 6,169, and the most part went to patients with tumor size > 5 cm who were 6,779. In terms of age, 61-70 years old (33.8%) was the most common patient, and 51-60 years old (41.0%) was the most common among patients with tumors ≤ 2 cm, 61-70 years old (36.9%) was the most common among patients with tumor size 2-5 cm, and over 70 years old (36.4%) was the most common among patients with tumor size > 5 cm. In all three tumor size subgroups, males accounted for the largest proportion (72.8%, 75.7%, and 78.1%). A large proportion of study were white (68.6%), and the majority of the patients were white in diferent tumor sizes (72.1%, 69.6%, and 66.9%). For tumor stage, patients with tumor size ≤2 cm (61.2%) and 2-5 cm (53.6%) had the most patients in the stage I, and patients with tumors greater than 5 cm had the most patients in the stage III (37.5%). Patients with tumor size ≤2 cm (63.5%) and 2-5 cm (56.5%) had the most at stage T1, while patients with tumor size > 5 cm (49.6%) had the most at stage T3. In the three tumor size groups, patients at stage N0 and stage M0 had the largest proportion. Patients with tumor size ≤2 cm (66.0%) and 2-5 cm (53.3%) were more likely to have had surgery, while patients with tumor size > 5 cm (74.5%) were have no surgery or unknown conditions. Among the subgroups of diferent tumor sizes, the percentage of patients who did not undergo chemotherapy, radiation, or unknown conditions were higher. For the HCC-special survival liver cancer patients, the distribution of each factor in diferent tumor sizes was consistent with OS.

Cox Proportional Hazards
Model. Univariate and multivariate analyses details are shown in Table 2. Te results showed that all factors (P < 0.001), including age, gender, race, marital status, tumor size, AJCC stage, TNM stage, surgery, radiation, and chemotherapy (P � 0.049), were signifcant prognostic factors for OS and specifc survival.
In multivariable analysis, the male (HR � 1.06, 95% CI: 1.01-1.12) was more likely to get cancer than the female. Te risk increases when patients are older than 50, and they are most likely to develop the disease when they were older than 70 (HR � 1.40, 95% CI: 1.28-1.53). Among race  European Journal of Cancer Care Figure 2 shows that survival was higher in patients who underwent suboptimal treatment (combination of three treatments: surgery plus chemotherapy, surgery plus radiotherapy, and only surgery) during the frst 20 months and highest after 80 months in patients who underwent surgery alone and in combination with chemotherapy but very low in patients who underwent radiotherapy combined with chemotherapy or no treatment at all. Figures 2(a) and 2(b) display the rate of overall and special survival with HCC using univariable and multivariable analyses. Figures 2(a) and 2(b) show that only surgery and surgery plus chemotherapy were the most efective intervention therapy for overall and special survival. Figure 3 shows the survival of patients with tumor size ≤2 cm, 2-5 cm, and > 5 cm under diferent treatment strategies, respectively. In each tumor size study, patients who underwent surgery and surgery plus chemotherapy had the highest survival rates within 80 months (Figure 3). Figures 3(a), 3(c), and 3(e) illustrate that the survival rate of patients undergoing surgery or undergoing surgery plus chemotherapy was higher, while the survival rate of patients receiving no treatment was always lower than that of patients receiving diferent treatment strategies in all three diferent tumor sizes for HCC-OS. On the other aspects, Figures 3(b), 3(d), and 3(f ) illustrate HCC-specifc survival in diferent treatment strategies. Figure 3(b) displays that the survival rate of patients receiving surgery alone and surgery plus chemotherapy was higher than that of other patients up to the frst 80 months for tumor size ≤2 cm. Figure 3(d) demonstrates that the survival rate of patients undergoing surgery plus chemotherapy and surgery plus radiotherapy in the frst 80 months was basically higher than that of other patients, while the survival rate of patients receiving no treatment was the lowest for tumor size 2-5 cm. Figure 3 Figure 5 shows that tumor size was positively correlated with a mortality rate of HCC. Figure 5 displays that the change rate of the mortality rate's HR increased rapidly during the period of 1-12 cm. Afterwards, the mortality rate's HR basically and smoothly was maintained at a high level.

Discussion
HCC is a malignant tumor frequently seen worldwide with an extremely high mortality rate [1]. Terefore, the accurate diagnosis and the most appropriate treatment are crucially important. Senior patients were often considered to be the easy targets because of complex diseases and altered drug metabolism. Aging and chromosomal changes within the liver were proofed to be connected. Otherwise, shortening of the telomeres is also associated with aging in the liver [14]. DNA copy number changes, gene mutations, a weak immune system, and limited treatment options are a combination which can lead to lower survival rates in senior patients [15]. Te past 3 decades of experimental studies have witnessed the death rate of people ≥ 60 years with liver cancer sharply increasing in more than 50% of people worldwide [16]. Previous cohort analyses had found a gradual increase in the mortality of HCC patients aged ≥ 75 years [17]. Scientists proofed that male population was prone to develop HCC than the female worldwide [18]. Social activities of males in life were more than that of females and drinking was inevitable in social situations, the action of which contributes to the generation and acceleration of reactive oxygen species. Tese highly reactive particles may have a huge impact on your organs and readily deposited in the brain, liver, heart, and kidneys [19]. Recent studies have shown alcoholics of all ages were subjected to elevated blood endotoxin levels, more active infammatory cascades, and increased oxidative stress and lipid peroxidation [20]. Meanwhile, inherent diversities in genes and hormone levels between both genders were also contributing to these factors [16]. In the 2013 investigation, 21,143 male and 8,330 female from the US were diagnosed with HCC, and male deaths of HCC also increased the most during the year [21]. According to the latest estimates from the World Health Organization, the death toll of the male patients was 2.35 times more than that of the women [22].
In the expert's study from 2003 to 2009, the absolute rate of HCC increased by 2.6 percent for whites and 2.3 percent for blacks [21]. Tis conclusion was consistent with the conclusion of our study that whites stand higher possibility. On the contrary, other studies had found that blacks were worse than whites in terms of insurance, medicaid, and the likelihood of having surgery.
Marriage had a benefcial efect on survival outcomes for primary liver cancer. Good survival outcomes for married people were not due to early detection; the reason was that unmarried women had lower rates of surgery and radiation than married women. Importantly, unmarried people were likely to have lower overall economic conditions than married populations; consequently, the disposable income they can spend on health care is relatively lower. Single cancer patients without a spouse who can provide adequate mental support and share the emotional burden had a higher risk of psychological distress, anxiety, and depression than married cancer patients.     26  774  944  150  1668  164  752  56   25  194  473  76  1482  62  648  47   15  139  312  38  1301  33  542  39   14  90  264  30  1067  21  511  34   14  81  207  26  1001  21  468    European Journal of Cancer Care In addition to the above factors, drug-related factors had also been noted. Te updated meta-analysis [23] demonstrated the benefcial chemoprophylaxis efect of statins on HCC development, which was dosedependent, was more obvious with lipophile statins. A systematic review and meta-analysis [24] supported the use of aspirin to reduce HCC incidence and liver-related mortality in high-risk populations, and HCC recurrence was lower after nonsteroidal anti-infammatory drugs treatment. Related research studies [25,26] found that type 2 diabetes mellitus had 3 times the risk of HCC. More controversial was the role of sulfonylureas in reducing HCC incidence in patients with diabetes [27].
Tis study showed that the 5-year survival rate in stage I of the AJCC for HCC was about 50%. HCC in stage I was nothing to be sneezed at, and the more advanced it was, the greater the risk was [28]. Patients diagnosed with HCC usually had obvious signs of cancer and liver failure. Te disease at the advanced stage was tough to be treated which makes most patients die within 3-6 months [29]. Surgery may be curative which coincided with this result in the early stages and had a better survival rate [30]. In our study, we had testifed that the bigger the tumor, the greater the risk. HCC features a growth with metastasis to distant organs. Bone metastasis may be the main manifestation of HCC, and it was very aggressive [31]. Te brain hemorrhage was the third prognostic factor for HCC patients. In the previous clinical study, the mortality rate of 10,000 HCC patients in Japan was HCC ≤ 2 cm (34%), 2-5 cm (48%), and HCC ≥ 5 cm (63%), which proofed that mortality increased with tumor growth. What is more, 5-year of all-cause mortality was about 50% [32]. It was widely accepted that patients with larger tumors had a worse prognosis than those with smaller tumors [2].
In other studies, patients who received liver transplantation had a 5-year OS rate up to 72%, suggesting that liver transplantation is an optimal treatment [33]. A study from Park et al. reported that among 224 inoperable nonmetastatic HCC patients, 1-year and 2-year locally progressfree rates were 97.4% in stereotactic ablative body radiotherapy, 83.8% in radiofrequency ablation, and 83.6% and 80.2% in radiofrequency ablation, respectively. Observational studies had displayed outcomes in patients with liver cancer treated with proton or carbon beam therapy with 90% control rate over 2-5 years [34]. Te study witnessed that survival rates were highest for patients who underwent surgery or who underwent surgery combined with other treatments in each size group.
At present, the main local treatment options include percutaneous ethanol injection, radiofrequency ablation, microwave ablation, cryoablation, and irreversible electroporation [35]. A propensity score matching analysis [36] revealed that the injection of ethanol near peritumoral vessels signifcantly reduced the risk of local tumor progression following peritumoral radiofrequency ablation of HCC. Radiofrequency ablation with 67-84% of 3year OS, 3.2-28.5% of 3-year local recurrence rates, and 90-98.5% of complete response for tumors < 3 cm was the  most commonly used medical technology [35]. Te cohort study [37] revealed that HCC within 3 cm and 3 nodules after operative microwave ablation had good long-term outcomes. Systematic review and meta-analysis [38] indicated that the microwave ablation had superiority in larger neoplasms. A prospective single-center study [39] with a total of 26 participants and 39 tumors showed for the frst time that percutaneous irreversible  25  23  16  11  11  1335  401  227  135  120  1220  611  390  268  244  203  118  51  41  37  2768  2435  1938  1661  1495  100  51  24  18  18  746  627  507  448  395  55  43  32  25  electroporation was a safe and efective ablation technology for HCC abutting the diaphragm. A narrative review [40] disclosed that palliative care had the potential to improve outcomes for HCC. In addition, liver transplantation ofered a glimmer of hope and possibility for patients with advanced HCC. Clinical decision makers can refer to the results from this study when choosing the ideal treatment options which can enhance efectiveness and decline the time and cost for the treatment.
Tere were certain limitations though. It referred to chemotherapy in the study as a generalization, without specifc classifcation studies, including the timing of medication, drug selection and compatibility, drug order, drug dosages, course of treatment, and interval time. In addition, lack of information about specifc treatment options for HCC, including liver surgery, liver transplantation, radiotherapy, percutaneous ethanol injection, transarterial chemoembolization, microwave ablation, radiofrequency ablation, postoperative adjuvant chemoradiotherapy, nutrition supportive therapy, and palliative care, can lead to instability and bias in outcomes. Furthermore, some other factors were not mentioned in this article, such as alcohol consumption, obesity, diabetes, income, whether the patient was exposed to afatoxin-contaminated food, and so on. Despite these limitations, the results from this study generally proved the relationship between tumor size and survival prognosis and testifed to the relatively optimal treat proposal for HCC.

Conclusions
Tis study revealed that the age of majority in HCC was over 50 years old, and the majority of HCC had solid tumor sizes of 2-5 cm and not otherwise specifed histology. Te incidence of HCC in males was much higher than that in females, and whites also proved to be more than half the population at risk for HCC. Based on diferent stages, the majority of patients were in the early stages of HCC. Furthermore, HCC patients were distributed in above 2 cm, and the distribution of basic information for diferent tumor sizes was consistent with the overall populations. Single patients had more challenges than married patients. Otherwise, survival rates were greater in patients with tumor size ≤2 cm who underwent surgery or surgery with chemotherapy. Patients with HCC in the early stage had a higher survival probability, particularly when they had undergone surgery or surgery plus chemotherapy. Te most important thing was that we further determined that the larger the tumor, the greater the risk, and that surgical treatment was the major and critical of the three methods.

Ethical Approval
Tis study has been approved by the institution review board (IRB), and there are no ethical requirements involved (KY 2022-002-05).

Disclosure
He Zheng and Zilin Chen are the co-frst authors. All funders had no roles in study design, data collection and analysis, decision to publish, or preparation of the manuscript.