Key Points
Question
What are the risk factors, patterns, and outcomes of late recurrence (more than 2 years) after curative liver resection for hepatocellular carcinoma (HCC)?
Findings
In this multicenter study of 734 patients, among 303 patients who developed late HCC recurrence 2 years after liver resection for HCC, most had only intrahepatic recurrence and none had extrahepatic recurrence only; more than half of these patients received curative treatments, which included reresection, transplant, and local ablation. Late recurrence was associated with sex, cirrhosis, and several aggressive tumor characteristics of the initial HCC.
Meaning
The patterns of late recurrence suggest that surveillance for recurrence after 2 years of surgery should be targeted to the liver, and postoperative surveillance improved the chance of further potentially curative treatments, with resultant improved survival outcomes in patients with late recurrence.
This multicenter study investigates the risk factors, patterns, and outcomes of late recurrence after curative liver resection for hepatocellular carcinoma.
Abstract
Importance
Late recurrence (more than 2 years) after liver resection for hepatocellular carcinoma (HCC) is generally considered as a multicentric tumor or a de novo cancer.
Objective
To investigate the risk factors, patterns, and outcomes of late recurrence after curative liver resection for HCC.
Design, Setting, and Participants
This study was a multicenter retrospective analysis of patients who underwent curative liver resection for HCC at 6 hospitals in China from January 2001 to December 2015. Among 734 patients who were alive and free of recurrence at 2 years after resection, 303 patients developed late recurrence. Data were analyzed from June 2017 to February 2018.
Interventions
Liver resection for HCC.
Main Outcomes and Measures
Risk factors of late recurrence as well as patterns, treatments, and long-term outcomes of patients with late recurrence. Univariate and multivariate Cox regression analyses were performed to identify independent risk factors of late recurrence.
Results
Of the included 734 patients, 652 (88.8%) were male, and the mean (SD) age was 51.0 (10.3) years. At a median (interquartile range) follow-up of 78.0 (52.8-112.5) months, 303 patients (41.3%) developed late recurrence. Multivariate analysis revealed that male sex, cirrhosis, multiple tumors, satellite nodules, tumor size greater than 5 cm, and macroscopic and microscopic vascular invasion were independent risk factors of late recurrence. Of the 303 patients with late recurrence, 273 (90.1%) had only intrahepatic recurrence, 30 (9.9%) had both intrahepatic and extrahepatic recurrence, and none had only extrahepatic recurrence. Potentially curative treatments were given to 165 of 303 patients (54.5%) with late recurrence, which included reresection, transplant, and local ablation. Multivariate Cox regression analysis showed that regular surveillance for postoperative recurrence (hazard ratio [HR], 0.470; 95% CI, 0.310-0.713; P = .001), cirrhosis (HR, 1.381; 95% CI, 1.049-1.854; P = .02), portal hypertension (HR, 2.424; 95% CI, 1.644-3.574; P < .001), Child-Pugh grade of B or C (HR, 1.376; 95% CI, 1.153-1.674; P < .001), Barcelona Clinic Liver Cancer stage B (HR, 1.304; 95% CI, 1.007-1.708; P = .04) and stage C (HR, 2.037; 95% CI, 1.583-2.842; P < .001), and potentially curative treatment (HR, 0.443; 95% CI, 0.297-0.661; P < .001) were independent predictors of overall survival for patients with late recurrence.
Conclusions and Relevance
Late recurrence after HCC resection was associated with sex, cirrhosis, and several aggressive tumor characteristics of the initial HCC. The patterns of late recurrence suggested surveillance for recurrence after 2 years of surgery should be targeted to the liver. Postoperative surveillance improved the chance of potentially curative treatments, with improved survival outcomes in patients with late recurrence.
Introduction
Hepatocellular carcinoma (HCC) is a common malignancy, ranking sixth among the most common neoplasms and third among the leading causes of cancer-related mortality worldwide.1,2,3,4 In China, HCC ranks second only to lung cancer in cancer-related deaths.5 Liver resection remains the mainstay of curative treatment.6,7 The long-term prognosis after HCC resection still remains unsatisfactory because of the high rate of cancer recurrence of up to 60% to 70% in patients within 5 years after surgery.8,9,10,11 Identifying risk factors of recurrence is of vital importance to improve long-term survival outcomes after HCC resection.
Hepatocellular carcinoma recurrence is divided into early recurrence (less than 2 years) and late recurrence (more than 2 years) according to the time to recurrence after surgery.8,12,13 Early recurrence within 2 years after surgery is most likely the consequence of occult metastasis from the initial tumor, whereas late recurrence after 2 years postsurgery is often of clonal origin, which is different from the original tumor, suggesting a de novo second primary HCC.14,15,16 Numerous previous studies have showed that early recurrence is commonly associated with aggressive tumor pathological characteristics, such as large tumor size, multiple tumors, poor cell differentiation, macroscopic and microscopic vascular invasion, and satellite lesions.17,18,19,20,21,22,23 Reported studies on late recurrence are less frequent and are typically single-center studies with small sample sizes. These studies reported that late recurrence is usually associated with underlying liver conditions, like cirrhosis and active hepatitis.15,24 To our knowledge, the patterns of late recurrence, treatment, and long-term survival outcomes in patients with late recurrence have not been studied.
A large multicenter study was conducted to investigate the risk factors, patterns, and predictors of long-term survival outcomes in patients with late recurrence. The study aimed to provide data to clinicians to plan surveillance of recurrence and to determine the strategy of treatment.
Methods
Patient Selection
With approval of the institutional review board at each study center, a retrospective study was conducted on patients who underwent curative liver resection for HCC at 6 hospitals in China from January 2001 to December 2015. All these patients had resectable tumors, adequate liver remnant sizes with good liver function, and absence of distant metastasis. Curative resection was defined as removal of all tumor with a clear margin (R0 resection). Patients with recurrent HCC or combined HCC and cholangiocarcinoma as well as patients who received preoperative antitumor treatment were excluded. Patients who died or developed HCC recurrence within 2 years after surgery were also excluded, as this study focused on late recurrence. The study was censored on December 31, 2017. Written informed consent was obtained from all the patients for their data to be used in clinical research. This study was performed in accordance with the Declaration of Helsinki25 and the Ethical Guidelines for Clinical Studies for all the study centers.
Clinicopathological Variables
Risk factors of late recurrence were evaluated as categories related to the patient, tumor, and treatment. Patient-related factors included age, sex, performance status, comorbid illness, etiology of liver disease, presence of cirrhosis or portal hypertension, Child-Pugh grading, preoperative α-fetoprotein (AFP) level, and preoperative alanine aminotransferase and aspartate aminotransferase levels. Comorbid illnesses included hypertension, diabetes, cardiovascular disease, chronic obstructive pulmonary disease, and renal dysfunction. Cirrhosis was confirmed by histopathological examination of the noncancerous part of the resected specimens. Portal hypertension was defined by the presence of either esophageal varices or splenomegaly with a decreased platelet count (100 × 103/μL or less). Tumor factors included tumor number, satellite lesions, maximum tumor size, macroscopic or microscopic vascular invasion, tumor differentiation, and tumor staging. Surgery-related factors included intraoperative blood loss, intraoperative blood transfusion, extent of resection (major or minor), type of resection (anatomical or nonanatomical), and width of resection margin. Major hepatectomy was defined as resection of 3 or more Couinaud segments, while minor hepatectomy as resection of fewer than 3 Couinaud segments. Anatomical resections were defined by the Brisbane 2000 nomenclature of liver anatomy,26 while nonanatomical resections included wedge resection or limited resection.
Follow-up
For patients with chronic hepatitis B virus (HBV) infection, when the preoperative HBV DNA level was 1000 copies/mL or greater, oral adjuvant antiviral therapy with lamivudine, 100 mg, adefovir dipivoxil, 10 mg, or entecavir, 0.5 mg, daily was commenced after discussion with the patient. Patients were prospectively followed up at each center using a surveillance strategy adopted by all the centers for recurrence. After hospital discharge, patients were followed up using serum AFP level as well as ultrasonography, contrast-enhanced computed tomography (CT), or magnetic resonance imaging of the chest and abdomen once every 2 months for 6 months and then once every 3 months for the next 1.5 years. Recurrence surveillance at 6-month intervals was carried out for patients who were alive and free of cancer recurrence 2 years after surgery.
Regular surveillance was defined as abdominal imaging and/or AFP surveillance every 6 months or within 6 months prior to the diagnosis of HCC recurrence, while irregular surveillance was defined as surveillance with intervals greater than 6 months or diagnosis of HCC recurrence because of symptoms or because the patient was investigated for other reasons. Tumor recurrence was suspected with progressive elevation of serum AFP levels and ultrasonographic detection of a new hepatic lesion. The diagnosis was made when dynamic CT or magnetic resonance imaging showed contrast enhancement in the arterial phase and washout in the venous phase or when hepatic angiography disclosed high tumor vascularity. Once tumor recurrence was suspected, patients were hospitalized to confirm the diagnosis. Appropriate management included reresection, liver transplant, local ablation therapy, transcatheter arterial chemoembolization, oral sorafenib, radiotherapy, and supportive therapy. Reresection, liver transplant, and local ablation therapy were considered potentially curative treatments, while the other treatments were considered noncurative. Details documented at the time of the first recurrence included the recurrence patterns and primary treatment modality. The dates of tumor recurrence, last follow-up, and death were recorded.
Statistical Analysis
Clinical and pathological characteristics were summarized using frequencies and percentages for categorical covariates and medians and ranges for continuous covariates. The Fisher exact test was used to compare categorical covariates, while continuous covariates were compared with the Wilcoxon rank sum test. The cutoffs for continuous variables were chosen for easy interpretation. The overall survival (OS) and recurrence-free survival were calculated with the Kaplan-Meier method. Univariate and multivariable Cox regression analyses were used to identify the independent risk factors of late recurrence. Variables with P values less than .10 on univariate analysis were subjected to the multivariate Cox regression model using a forward stepwise variable selection. Subgroup analyses were made in patients who developed late recurrence of HCC. Multivariate analysis was used to evaluate predictors associated with long-term survival in patients with late recurrence. Statistical analyses were performed using SPSS version 25.0 (IBM). A 2-tailed P value less than .05 was considered statistically significant for all the tests.
Results
Occurrence of Late Recurrence
Of the 734 patients who were alive and free of cancer recurrence at 2 years after surgery enrolled in this multicenter retrospective study (eFigure in the Supplement), 652 (88.8%) were male and 82 (11.2%) were female; 671 patients (91.4%) had chronic HBV infection and 22 patients (3.0%) were positive for hepatitis C virus RNA. Among 671 patients with chronic HBV infection, 345 (51.4%) patients had a positive preoperative HBV DNA level (1000 copies/mL or greater), and 326 (48.6%) patients had a negative preoperative HBV DNA level (less than 1000 copies/mL). Pathological examination showed that 489 patients (66.6%) had cirrhosis, and 227 (30.9%) had portal hypertension.
During a median follow-up of 78.0 months, 303 of 734 patients (41.3%) developed late recurrence. Comparisons of the baseline characteristics and operative variables between patients with and without late recurrence are illustrated in Table 1. There were significant differences between these 2 groups in the etiology of liver disease, cirrhosis, satellite nodules, macroscopic and microscopic vascular invasion, tumor differentiation, type of hepatectomy, and width of resection margin. For the 671 patients with chronic HBV infection, late recurrence occurred in 345 patients with a preoperative positive HBV DNA level, which was higher than that in 326 patients with a negative HBV DNA level (156 of 345 [45.2%] vs 129 of 326 [39.6%]), but the difference was not significant (P = .14). Also, late recurrence occurred less in patients who received antiviral therapy than those without antiviral therapy (177 of 439 [40.3%] vs 108 of 232 [46.6%]), but the difference was again not significant (P = .12).
Table 1. Comparison of Baseline Characteristics and Operative Variables Between Patients With and Without Late Recurrence After 2 Years of Curative Liver Resection for Hepatocellular Carcinoma.
| Variable | No. (%) | P Value | ||
|---|---|---|---|---|
| Total (N = 734) | With Late Recurrence (n = 303) | Without Late Recurrence (n = 431) | ||
| Age, mean (SD), y | 51.0 (10.3) | 50.9 (9.6) | 51.1 (10.0) | .78 |
| Sex | .84 | |||
| Male | 652 (88.8) | 270 (89.1) | 382 (88.6) | |
| Female | 82 (11.2) | 33 (10.9) | 49 (11.4) | |
| Performance status | .15 | |||
| 0 | 475 (64.7) | 187 (61.7) | 288 (66.8) | |
| 1 | 259 (35.3) | 116 (38.3) | 143 (33.2) | |
| Comorbid illnessa | 148 (20.2) | 71 (23.4) | 77 (17.9) | .06 |
| Etiology of liver disease | .002 | |||
| HBV | 662 (90.2) | 278 (91.7) | 384 (89.1) | |
| HCV | 22 (3.0) | 15 (5.0) | 7 (1.6) | |
| HBV and HCV | 9 (1.2) | 7 (2.3) | 2 (0.5) | |
| Other | 59 (8.0) | 17 (5.6) | 42 (9.7) | |
| Cirrhosis | 489 (66.6) | 222 (73.3) | 267 (61.9) | .001 |
| Portal hypertension | 227 (30.9) | 89 (29.4) | 138 (32.0) | .45 |
| Child-Pugh grade | .75 | |||
| A | 678 (92.4) | 281 (92.7) | 397 (92.1) | |
| B | 56 (7.6) | 22 (7.3) | 34 (7.9) | |
| Preoperative AFP level, ng/mL | .54 | |||
| ≤400 | 513 (69.9) | 208 (68.6) | 305 (70.8) | |
| >400 | 221 (30.1) | 95 (31.4) | 126 (29.2) | |
| Preoperative ALT level, median (range), U/L | 41.9 (8.5-514.6) | 43.6 (14.2-514.6) | 39.9 (8.5-467.2) | .28 |
| Preoperative AST level, median (range), U/L | 36.8 (13.3-512.0) | 39.6 (15.4-512.0) | 35.0 (13.3-414.3) | .30 |
| Tumor No. | .06 | |||
| Solitary | 629 (85.7) | 251 (82.8) | 378 (87.7) | |
| Multiple | 105 (14.3) | 52 (17.2) | 53 (12.3) | |
| Satellite nodules | 105 (14.3) | 56 (18.5) | 49 (11.4) | .007 |
| Maximum tumor size, mean (SD), cm | 5.1 (3.3) | 5.4 (3.5) | 4.9 (3.1) | .06 |
| Vascular invasion | ||||
| Macroscopic | 14 (1.9) | 11 (3.6) | 3 (0.7) | .004 |
| Microscopic | 326 (44.4) | 154 (50.8) | 172 (39.9) | .003 |
| Poor cell differentiation | 552 (75.2) | 249 (82.2) | 303 (70.3) | <.001 |
| BCLC tumor stage | .06 | |||
| A | 316 (43.1) | 115 (38.0) | 201 (46.6) | |
| B | 184 (25.1) | 82 (27.1) | 102 (23.7) | |
| C | 234 (31.9) | 106 (35.0) | 128 (29.7) | |
| Intraoperative blood loss, median (range), mL | 300 (30-3000) | 250 (50-3000) | 300 (30-3000) | .50 |
| Intraoperative blood transfusion | 100 (13.6) | 47 (15.5) | 53 (12.3) | .21 |
| Extent of hepatectomy | .08 | |||
| Major | 133 (18.1) | 64 (21.1) | 69 (16.0) | |
| Minor | 601 (81.8) | 239 (78.9) | 362 (84.0) | |
| Type of hepatectomy | .04 | |||
| Anatomical | 220 (30.0) | 78 (25.7) | 142 (32.9) | |
| Nonanatomical | 514 (70.0) | 225 (74.3) | 289 (67.1) | |
| Resection margin | <.001 | |||
| ≤1 cm | 164 (22.3) | 97 (32.0) | 67 (15.5) | |
| >1 cm | 570 (77.7) | 206 (68.0) | 364 (84.5) | |
Abbreviations: AFP, α-fetoprotein; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BCLC, Barcelona Clinic Liver Cancer; HBV, hepatitis B virus; HCV, hepatitis C virus.
SI conversion factors: To convert AFP to micrograms per liter, multiply by 1; ALT to microkatals per liter, multiply by 0.0167; AST to microkatals per liter, multiply by 0.0167.
Comorbid illnesses include hypertension, diabetes, cardiovascular disease, chronic obstructive pulmonary disease, and renal dysfunction.
Risk Factors of Late Recurrence
Univariate and multivariate Cox regression analyses predicted late recurrence in patients who were alive and free of recurrence at 2 years after curative liver resection of HCC. Multivariate analysis identified that male sex (hazard ratio [HR], 1.372; 95% CI, 1.022-1.875; P = .04), cirrhosis (HR, 1.421; 95% CI, 1.096-1.843; P = .008), multiple tumors (HR, 1.559; 95% CI, 1.138-2.136; P = .006), satellite nodules (HR, 1.587; 95% CI, 1.127-2.165; P = .004), maximum tumor size greater than 5 cm (HR, 1.487; 95% CI, 1.104-2.003; P = .009), macroscopic vascular invasion (HR, 4.631; 95% CI, 2.475-8.667; P < .001), and microscopic vascular invasion (HR, 1.686; 95% CI, 1.254-2.266; P = .001) were independent risk factors of late recurrence (Table 2).
Table 2. Univariate and Multivariate Cox Regression Analyses of Time to Late Recurrence in Patients Who Were Alive and Free of Recurrence at 2 Years After Curative Liver Resection of Hepatocellular Carcinoma.
| Variable | Comparison | Univariate | Multivariate | ||
|---|---|---|---|---|---|
| HR (95% CI) | P Valuea | HR (95% CI) | P Value | ||
| Age | ≤60 vs >60 y | 1.295 (0.951-1.764) | .10 | NA | NA |
| Sex | Male vs female | 1.460 (1.065-2.007) | .02 | 1.372 (1.022-1.875) | .04 |
| Performance status | 0 vs 1 | 1.313 (1.041-1.655) | .02 | NS | .37 |
| Comorbid illness | Yes vs no | 1.285 (0.933-1.776) | .12 | NA | NA |
| Etiology of liver disease | HBV vs non-HBV | 1.387 (0.921-2.090) | .12 | NA | NA |
| Cirrhosis | Yes vs no | 1.518 (1.176-1.958) | .001 | 1.421 (1.096-1.843) | .008 |
| Portal hypertension | Yes vs no | 0.980 (0.765-1.255) | .87 | NA | NA |
| Child-Pugh grade | A vs B | 1.213 (0.786-1.874) | .38 | NA | NA |
| Preoperative AFP level | ≤400 vs >400 ng/mL | 1.154 (0.905-1.471) | .25 | NA | NA |
| Preoperative ALT level | ≤40 vs >40 U/L | 1.265 (1.007-1.588) | .04 | NS | .27 |
| Preoperative AST level | <40 vs >40 U/L | 1.357 (1.082-1.701) | .008 | NS | .20 |
| Tumor No. | Solitary vs multiple | 1.693 (1.254-2.285) | .001 | 1.559 (1.138-2.136) | .006 |
| Satellite nodules | Yes vs no | 1.877 (1.402-2.512) | <.001 | 1.587 (1.127-2.165) | .004 |
| Maximum tumor size | ≤5 vs >5 cm | 1.419 (1.130-1.784) | .003 | 1.487 (1.104-2.003) | .009 |
| Macroscopic vascular invasion | Yes vs no | 4.800 (2.618-8.802) | <.001 | 4.631 (2.475-8.667) | <.001 |
| Microscopic vascular invasion | Yes vs no | 1.425 (1.137-1.786) | .002 | 1.686 (1.254-2.266) | .001 |
| Poor cell differentiation | Yes vs no | 1.735 (1.293-2.329) | <.001 | NS | .12 |
| Intraoperative blood loss | ≤400 vs >400 mL | 0.959 (0.751-1.225) | .74 | NA | NA |
| Intraoperative blood transfusion | Yes vs no | 1.354 (0.992-1.849) | .06 | NS | .13 |
| Extent of hepatectomy | Major vs minor | 1.409 (1.069-1.857) | .02 | NS | .22 |
| Type of hepatectomy | Anatomical vs nonanatomical | 0.798 (0.617-1.033) | .09 | NS | .13 |
| Resection margin | ≤1 vs >1 cm | 1.507 (1.080-2.013) | .009 | NS | .25 |
Abbreviations: AFP, α-fetoprotein; ALT, alanine aminotransferase; AST, aspartate aminotransferase; HBV, hepatitis B virus; HR, hazard ratio; NA, not applicable; NS, not significant.
SI conversion factors: To convert AFP to micrograms per liter, multiply by 1; ALT to microkatals per liter, multiply by 0.0167; AST to microkatals per liter, multiply by 0.0167.
Variables with a P value less than .10 in univariate analysis were subjected to multivariate Cox regression model using forward stepwise variable selection.
Patterns of Late Recurrence
Among the 303 patients who developed late recurrence, 273 (90.1%) were first diagnosed to have intrahepatic recurrence only and 30 (9.9%) to have intrahepatic and extrahepatic recurrence. There were no patients who had extrahepatic metastases only without intrahepatic recurrence.
Treatments and Outcomes of Late Recurrence
Of the 303 patients who developed late recurrence, 165 patients (54.5%) underwent potentially curative treatments, which included reresection (n = 113), liver transplant (n = 14), and local ablation (n = 38). The remaining 138 patients had advanced tumor staging and/or poor liver function, and they underwent palliative treatments, which included transcatheter arterial chemoembolization (n = 29), radiotherapy (n = 10), sorafenib (n = 28), combined treatment modalities (n = 59), and supportive care (n = 12). Figure 1 shows that the Kaplan-Meier OS curves in patients with late recurrence were significantly poorer than those without.
Figure 1. Overall Survival Curves of Patients With and Without Late Recurrence.
Postoperative Recurrence Surveillance in Patients With Late Recurrence
In 303 patients who developed late recurrence, 140 patients (46.2%) underwent postoperative regular surveillance for recurrence. Of the 163 patients (53.8%) who underwent irregular surveillance, 112 patients were diagnosed as having late HCC recurrence because of symptoms. Comparisons of the baseline characteristics, treatment modalities, and survival outcomes between patients with regular and irregular recurrence surveillance are illustrated in Table 3. There were significant differences between these 2 groups in the number of patients with cirrhosis, portal hypertension, and serum AFP positivity on first diagnosis of late recurrence and tumor staging, patterns of late recurrence, and deaths during follow-up. The percentage of patients who underwent potentially curative treatment in the regular surveillance group was significantly higher than that in the irregular surveillance group (76.4% vs 35.6%; P < .001). The median OS in patients who underwent regular recurrence surveillance was significantly longer than in patients who underwent irregular recurrence surveillance (66.6 vs 20.2 months; HR, 0.306; 95% CI, 0.224-0.418; P < .001) (Figure 2).
Table 3. Comparison of Baseline Characteristics, Treatment Modalities, and Outcomes of 303 Patients With Late Recurrence of Hepatocellular Carcinoma Between Those Under Regular and Irregular Recurrence Surveillance.
| Variable | No. (%) | P Value | ||
|---|---|---|---|---|
| Total (n = 303) | Regular Surveillance (n = 140) | Irregular Surveillance (n = 163) | ||
| Age at diagnosis of recurrence, mean (SD), y | 55.7 (9.8) | 55.8 (9.5) | 55.7 (10.1) | .95 |
| Sex | .93 | |||
| Male | 270 (89.1) | 125 (89.3) | 145 (89.0) | |
| Female | 33 (10.9) | 15 (10.7) | 18 (11.0) | |
| Comorbid illness | 102 (33.7) | 43 (30.7) | 59 (36.2) | .31 |
| Etiology of liver disease | .07 | |||
| HBV | 278 (91.7) | 135 (96.4) | 143 (87.7) | |
| HCV | 15 (5.0) | 5 (3.6) | 10 (6.1) | |
| HBV and HCV | 7 (2.3) | 3 (2.1) | 4 (2.5) | |
| Other | 17 (5.6) | 3 (2.1) | 14 (8.6) | |
| Cirrhosis at the diagnosis of recurrence | 245 (80.9) | 106 (75.7) | 139 (85.3) | .04 |
| Portal hypertension at the diagnosis of recurrence | 113 (37.3) | 38 (27.1) | 75 (46.0) | .001 |
| Child-Pugh grade at the diagnosis of recurrence | .66 | |||
| A | 265 (87.5) | 124 (88.6) | 141 (86.5) | |
| B | 34 (11.2) | 15 (10.7) | 19 (11.7) | |
| C | 4 (1.3) | 1 (0.7) | 3 (1.8) | |
| Serum AFP level, ng/mL | <.001 | |||
| ≤400 | 196 (64.7) | 105 (75.0) | 91 (55.8) | |
| >400 | 107 (35.3) | 35 (25.0) | 72 (44.2) | |
| BCLC tumor stage of late recurrence | <.001 | |||
| A | 124 (40.9) | 79 (56.4) | 45 (27.6) | |
| B | 101 (33.3) | 33 (23.6) | 68 (41.7) | |
| C | 78 (25.7) | 28 (20.0) | 50 (30.7) | |
| Patterns of late recurrence | .001 | |||
| Intrahepatic recurrence | 273 (90.1) | 135 (96.4) | 138 (84.7) | |
| Intrahepatic and extrahepatic recurrence | 30 (9.9) | 5 (3.6) | 25 (15.3) | |
| Treatment modality | <.001 | |||
| Potentially curative treatment | 165 (54.5) | 107 (76.4) | 58 (35.6) | |
| Noncurative treatment | 138 (45.5) | 33 (23.6) | 105 (64.4) | |
| Deaths during the follow-up | 182 (60.1) | 74 (52.9) | 108 (66.3) | .02 |
| OS from recurrence diagnosis, mean (SD), mo | 63.3 (4.6) | 85.8 (6.7) | 38.2 (5.2) | <.001 |
| 1-y OS rate, % | 78.7 | 95.7 | 63.6 | |
| 3-y OS rate, % | 51.5 | 72.5 | 30.1 | |
| 5-y OS rate, % | 36.6 | 56.2 | 14.9 | |
Abbreviations: AFP, α-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; HBV, hepatitis B virus; HCV, hepatitis C virus; OS, overall survival.
SI conversion factor: To convert AFP to micrograms per liter, multiply by 1.
Figure 2. Overall Survival Curves of Patients With Late Recurrence Who Received Regular and Irregular Postoperative Surveillance.
Factors Associated With OS in Patients With Late Recurrence
Univariate and multivariate analyses of OS were performed to investigate the factors contributing to long-term survival outcomes in patients with late recurrence (eTable in the Supplement). Multivariate Cox regression analysis identified that postoperative surveillance for recurrence (regular vs irregular), cirrhosis (yes vs no), portal hypertension (yes vs no), Child-Pugh grading (A vs B or C), Barcelona Clinic Liver Cancer tumor staging of late recurrence (A vs B vs C), and treatment modality for late recurrence (potentially curative vs noncurative) were independent predictors of long-term OS outcomes in patients with late recurrence after liver resection for HCC.
Discussion
In this large multicenter retrospective study, late recurrence occurred in 41.3% of the 734 patients who were alive and free of tumor recurrence at 2 years after curative liver resection of HCC. Male sex, cirrhosis, multiple tumors, satellite nodules, tumor size greater than 5 cm, and macroscopic and microscopic vascular invasion were independent risk factors of late recurrence. In 303 patients with late recurrence, 273 (90.1%) had intrahepatic recurrence only, 30 (9.9%) had both intrahepatic and extrahepatic recurrence, and none had extrahepatic recurrence only. More than half of patients with late recurrence (165 of 303 [54.5%]) underwent potentially curative treatments for recurrent HCC. In addition, patients with late recurrence who were under regular recurrence surveillance compared with those who underwent irregular surveillance had significantly better chance to undergo potentially curative treatments for recurrent HCC (76.4% vs 35.6%), with more favorable long-term survival outcomes (median OS, 66.6 vs 20.2 months).
On univariate and multivariate Cox regression analysis, cirrhosis (HR, 1.421; 95% CI, 1.096-1.843; P = .008) was an independent risk factor of late recurrence, which supported the hypothesis that late recurrence is more likely to be caused by multicentric tumors or de novo cancer formation from the underlying liver hepatitis and cirrhosis.13,15,18 In contrary to some studies,12,13,18 multiple tumors, satellite nodules, macroscopic and microscopic vascular invasion, and maximum tumor size greater than 5 cm were also independent risk factors of late recurrence, suggesting that late recurrence in our study was also correlated with the initial tumor. The use of 2 years after surgery as the cutoff point to differentiate metastasis from the initial tumor from de novo tumors is still controversial. Further novel histopathological examinations and genetic tests on both the initial and recurrent tumors are worth carrying out to find out whether recurrent tumors originate from the initial tumors.27,28
Interestingly, sex was found in this study to be an independent risk factor of late recurrence of HCC. Previous studies have shown men to be 3-fold to 8-fold more likely to develop HCC than women,29,30,31 and sex hormones are considered to be responsible for this sex difference.32,33,34,35 The sex difference in the late recurrence rate, which is often attributed to the multicentric origins of HCC, echoes the higher incidence of HCC in men than in women. This significant difference in late recurrence between sexes probably calls for closer and more stringent recurrence surveillance for men in the late period of postresection follow-up, which has also been proposed by Cucchetti et al.36 In addition, this finding also suggests that further research and trials are warranted to evaluate the potential value of sex hormone treatment, such as tamoxifen, as an adjuvant therapy for prevention of HCC recurrence in the future in female patients.
Understanding the patterns of HCC recurrence is important in designing surveillance and treatment strategies. No patients who developed late HCC recurrence had extrahepatic metastases without intrahepatic recurrences in our study. Thus, screening for extrahepatic metastasis using skeletal emission computerized tomography and chest CT is unnecessary for patients who have no intrahepatic recurrence. The current guidelines on HCC recurrence surveillance can be improved, and an individualized surveillance strategy should take account of the time from surgery and the patterns of recurrent tumor. This strategy is more cost-effective and provides a better balance between the benefit obtained from tumor surveillance and medical expenditure.
The prognosis in the 303 patients who developed late recurrence of HCC was different using different postoperative surveillance programs for recurrence. Multivariate Cox regression analysis demonstrated that regular recurrence surveillance was an independent protective factor of survival in patients with late recurrence (HR, 0.470; 95% CI, 0.310-0.713; P = .001). Regular postoperative recurrence surveillance is of vital importance because, in our study, it improved the chance of our patients to undergo curative treatment. In clinical practice, many patients do not take surveillance seriously and may as a consequence lose the chance to undergo curative treatment when symptoms develop.
Limitations
There are limitations in our study. First, this is a retrospective study, which has inherent biases. Second, this study came from China. Most patients with HCC had a background of HBV-related cirrhosis. In the United States and Europe, hepatitis C and excessive alcohol use are the main etiological factors of HCC.37,38 In addition, in some developed countries, nonalcoholic fatty liver disease is becoming an important etiology of HCC.39,40 Our study requires an external validation cohort to make the results more convincing, and the inclusion of such information is planned in our future studies.
Conclusions
In conclusion, this study showed sex, cirrhosis, multiple tumors, satellite nodules, maximum tumor size greater than 5 cm, and macroscopic and microscopic vascular invasion were independent risk factors of late recurrence of HCC. The patterns of late recurrence suggested that before the diagnosis of intrahepatic recurrence, screening for extrahepatic metastasis using chest CT and skeletal emission computerized tomography after 2 years of surgery is unnecessary. Regular surveillance improved the chance of patients to undergo potentially curative treatment at the time of diagnosis of late recurrence of HCC, thus contributing to better survival for these patients.
eTable. Univariate and multivariate analyses of overall survival in 303 patients with late recurrence after curative liver resection for hepatocellular carcinoma.
eFigure. CONSORT diagram of study population.
References
- 1.Yang JD, Roberts LR. Hepatocellular carcinoma: a global view. Nat Rev Gastroenterol Hepatol. 2010;7(8):448-458. doi: 10.1038/nrgastro.2010.100 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87-108. doi: 10.3322/caac.21262 [DOI] [PubMed] [Google Scholar]
- 3.Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet. 2012;379(9822):1245-1255. doi: 10.1016/S0140-6736(11)61347-0 [DOI] [PubMed] [Google Scholar]
- 4.Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018;391(10127):1301-1314. doi: 10.1016/S0140-6736(18)30010-2 [DOI] [PubMed] [Google Scholar]
- 5.Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66(2):115-132. doi: 10.3322/caac.21338 [DOI] [PubMed] [Google Scholar]
- 6.Bruix J, Gores GJ, Mazzaferro V. Hepatocellular carcinoma: clinical frontiers and perspectives. Gut. 2014;63(5):844-855. doi: 10.1136/gutjnl-2013-306627 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Chan AC, Poon RT, Ng KK, Lo CM, Fan ST, Wong J. Changing paradigm in the management of hepatocellular carcinoma improves the survival benefit of early detection by screening. Ann Surg. 2008;247(4):666-673. doi: 10.1097/SLA.0b013e31816a747a [DOI] [PubMed] [Google Scholar]
- 8.Imamura H, Matsuyama Y, Tanaka E, et al. Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J Hepatol. 2003;38(2):200-207. doi: 10.1016/S0168-8278(02)00360-4 [DOI] [PubMed] [Google Scholar]
- 9.Minagawa M, Makuuchi M, Takayama T, Kokudo N. Selection criteria for repeat hepatectomy in patients with recurrent hepatocellular carcinoma. Ann Surg. 2003;238(5):703-710. doi: 10.1097/01.sla.0000094549.11754.e6 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Zhang X, Li C, Wen T, et al. Appropriate treatment strategies for intrahepatic recurrence after curative resection of hepatocellular carcinoma initially within the Milan criteria: according to the recurrence pattern. Eur J Gastroenterol Hepatol. 2015;27(8):933-940. doi: 10.1097/MEG.0000000000000383 [DOI] [PubMed] [Google Scholar]
- 11.Hasegawa K, Kokudo N, Makuuchi M, et al. Comparison of resection and ablation for hepatocellular carcinoma: a cohort study based on a Japanese nationwide survey. J Hepatol. 2013;58(4):724-729. doi: 10.1016/j.jhep.2012.11.009 [DOI] [PubMed] [Google Scholar]
- 12.Poon RT, Fan ST, Ng IO, Lo CM, Liu CL, Wong J. Different risk factors and prognosis for early and late intrahepatic recurrence after resection of hepatocellular carcinoma. Cancer. 2000;89(3):500-507. doi: [DOI] [PubMed] [Google Scholar]
- 13.Portolani N, Coniglio A, Ghidoni S, et al. Early and late recurrence after liver resection for hepatocellular carcinoma: prognostic and therapeutic implications. Ann Surg. 2006;243(2):229-235. doi: 10.1097/01.sla.0000197706.21803.a1 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Zheng J, Chou JF, Gönen M, et al. Prediction of hepatocellular carcinoma recurrence beyond Milan criteria after resection: validation of a clinical risk score in an international cohort. Ann Surg. 2017;266(4):693-701. doi: 10.1097/SLA.0000000000002360 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Poon RT. Differentiating early and late recurrences after resection of HCC in cirrhotic patients: implications on surveillance, prevention, and treatment strategies. Ann Surg Oncol. 2009;16(4):792-794. doi: 10.1245/s10434-009-0330-y [DOI] [PubMed] [Google Scholar]
- 16.Du ZG, Wei YG, Chen KF, Li B. Risk factors associated with early and late recurrence after curative resection of hepatocellular carcinoma: a single institution’s experience with 398 consecutive patients. Hepatobiliary Pancreat Dis Int. 2014;13(2):153-161. doi: 10.1016/S1499-3872(14)60025-4 [DOI] [PubMed] [Google Scholar]
- 17.Huang L, Li J, Yan J, et al. Early recurrence after curative resection in oligonodular hepatocellular carcinoma. Hepatogastroenterology. 2013;60(121):28-31. [DOI] [PubMed] [Google Scholar]
- 18.Cheng Z, Yang P, Qu S, et al. Risk factors and management for early and late intrahepatic recurrence of solitary hepatocellular carcinoma after curative resection. HPB (Oxford). 2015;17(5):422-427. doi: 10.1111/hpb.12367 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Rou WS, Lee BS, Moon HS, Lee ES, Kim SH, Lee HY. Risk factors and therapeutic results of early local recurrence after transcatheter arterial chemoembolization. World J Gastroenterol. 2014;20(22):6995-7004. doi: 10.3748/wjg.v20.i22.6995 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Lee HY, Rhim H, Lee MW, et al. Early diffuse recurrence of hepatocellular carcinoma after percutaneous radiofrequency ablation: analysis of risk factors. Eur Radiol. 2013;23(1):190-197. doi: 10.1007/s00330-012-2561-8 [DOI] [PubMed] [Google Scholar]
- 21.Montasser MF, Shaker MK, Albreedy AM, Montasser IF, El Dorry A. Risk factors for early intrahepatic distant recurrence after radiofrequency ablation for hepatocellular carcinoma in Egyptian patients. J Dig Dis. 2014;15(12):676-683. doi: 10.1111/1751-2980.12190 [DOI] [PubMed] [Google Scholar]
- 22.Zhou YM, Yang JM, Li B, et al. Risk factors for early recurrence of small hepatocellular carcinoma after curative resection. Hepatobiliary Pancreat Dis Int. 2010;9(1):33-37. [PubMed] [Google Scholar]
- 23.Shimoda M, Tago K, Shiraki T, et al. Risk factors for early recurrence of single lesion hepatocellular carcinoma after curative resection. World J Surg. 2016;40(10):2466-2471. doi: 10.1007/s00268-016-3529-7 [DOI] [PubMed] [Google Scholar]
- 24.Yamamoto Y, Ikoma H, Morimura R, et al. Optimal duration of the early and late recurrence of hepatocellular carcinoma after hepatectomy. World J Gastroenterol. 2015;21(4):1207-1215. doi: 10.3748/wjg.v21.i4.1207 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.World Medical Association World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310(20):2191-2194. doi: 10.1001/jama.2013.281053 [DOI] [PubMed] [Google Scholar]
- 26.Strasberg SM, Phillips C. Use and dissemination of the Brisbane 2000 nomenclature of liver anatomy and resections. Ann Surg. 2013;257(3):377-382. doi: 10.1097/SLA.0b013e31825a01f6 [DOI] [PubMed] [Google Scholar]
- 27.Pecchi A, Besutti G, De Santis M, et al. Post-transplantation hepatocellular carcinoma recurrence: patterns and relation between vascularity and differentiation degree. World J Hepatol. 2015;7(2):276-284. doi: 10.4254/wjh.v7.i2.276 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Schmidt C, Marsh JW. Molecular signature for HCC: role in predicting outcomes after liver transplant and selection for potential adjuvant treatment. Curr Opin Organ Transplant. 2010;15(3):277-282. doi: 10.1097/MOT.0b013e328339837b [DOI] [PubMed] [Google Scholar]
- 29.White DL, Thrift AP, Kanwal F, Davila J, El-Serag HB. Incidence of hepatocellular carcinoma in all 50 United States, from 2000 through 2012. Gastroenterology. 2017;152(4):812-820.e5. doi: 10.1053/j.gastro.2016.11.020 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Lee CM, Lu SN, Changchien CS, et al. Age, gender, and local geographic variations of viral etiology of hepatocellular carcinoma in a hyperendemic area for hepatitis B virus infection. Cancer. 1999;86(7):1143-1150. doi: [DOI] [PubMed] [Google Scholar]
- 31.El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132(7):2557-2576. doi: 10.1053/j.gastro.2007.04.061 [DOI] [PubMed] [Google Scholar]
- 32.Villa E, Camellini L, Dugani A, et al. Variant estrogen receptor messenger RNA species detected in human primary hepatocellular carcinoma. Cancer Res. 1995;55(3):498-500. [PubMed] [Google Scholar]
- 33.De Maria N, Manno M, Villa E. Sex hormones and liver cancer. Mol Cell Endocrinol. 2002;193(1-2):59-63. doi: 10.1016/S0303-7207(02)00096-5 [DOI] [PubMed] [Google Scholar]
- 34.Nagasue N, Kohno H, Chang YC, et al. Androgen and estrogen receptors in hepatocellular carcinoma and the surrounding liver in women. Cancer. 1989;63(1):112-116. doi: [DOI] [PubMed] [Google Scholar]
- 35.Hassan MM, Botrus G, Abdel-Wahab R, et al. Estrogen replacement reduces risk and increases survival times of women with hepatocellular carcinoma. Clin Gastroenterol Hepatol. 2017;15(11):1791-1799. doi: 10.1016/j.cgh.2017.05.036 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Cucchetti A, Piscaglia F, Caturelli E, et al. Comparison of recurrence of hepatocellular carcinoma after resection in patients with cirrhosis to its occurrence in a surveilled cirrhotic population. Ann Surg Oncol. 2009;16(2):413-422. doi: 10.1245/s10434-008-0232-4 [DOI] [PubMed] [Google Scholar]
- 37.El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 2012;142(6):1264-1273.e1. doi: 10.1053/j.gastro.2011.12.061 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Morgan TR, Mandayam S, Jamal MM. Alcohol and hepatocellular carcinoma. Gastroenterology. 2004;127(5, suppl 1):S87-S96. doi: 10.1053/j.gastro.2004.09.020 [DOI] [PubMed] [Google Scholar]
- 39.Dyson J, Jaques B, Chattopadyhay D, et al. Hepatocellular cancer: the impact of obesity, type 2 diabetes and a multidisciplinary team. J Hepatol. 2014;60(1):110-117. doi: 10.1016/j.jhep.2013.08.011 [DOI] [PubMed] [Google Scholar]
- 40.Kanwal F, Kramer JR, Duan Z, Yu X, White D, El-Serag HB. Trends in the burden of nonalcoholic fatty liver disease in a United States cohort of veterans. Clin Gastroenterol Hepatol. 2016;14(2):301-308.e1, 2. doi: 10.1016/j.cgh.2015.08.010 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eTable. Univariate and multivariate analyses of overall survival in 303 patients with late recurrence after curative liver resection for hepatocellular carcinoma.
eFigure. CONSORT diagram of study population.