Evidence of relative effectiveness of local treatments for hepatocellular carcinoma (HCC) is scanty. We investigated, in a retrospective cohort study, whether surgical resection, radiofrequency ablation (RFA), percutaneous ethanol injection (PEI), and transarterial embolization with (TACE) or without (TAE) chemotherapy resulted in different survival in clinical practice. All patients first diagnosed with HCC and treated with any locoregional therapy from 1998 to 2002 in twelve Italian hospitals were eligible. Overall survival (OS) was the unique endpoint. Three main comparisons were planned: RFA versus PEI, surgical resection versus RFA/PEI (combined), TACE/TAE versus RFA/PEI (combined). Propensity score method was used to minimize bias related to non random treatment assignment. Overall 425 subjects were analyzed, with 385 (91%) deaths after a median followup of 7.7 years. OS did not significantly differ between RFA and PEI (HR 1.11, 95% CI 0.79–1.57), between surgery and RFA/PEI (HR 0.95, 95% CI 0.64–1.41) and between TACE/TAE and RFA/PEI (HR 0.88, 95% CI 0.66–1.17). 5-year OS probabilities were 0.14 for RFA, 0.18 for PEI, 0.27 for surgery, and 0.15 for TACE/TAE. No locoregional treatment for HCC was found to be more effective than the comparator. Adequately powered randomized clinical trials are still needed to definitely assess relative effectiveness of locoregional HCC treatment.
Locoregional treatments are the mainstay of treatment of early stage hepatocellular carcinoma (HCC) [
A meta-analysis [
Two meta-analyses [
Three meta-analyses [
In general, these studies were conducted in specialized reference centers in well-selected patients. In this observational cohort study we assessed the relative effectiveness on long-term survival of locoregional treatments for HCC in real-world patients.
The study had a retrospective cohort design. All patients first diagnosed with HCC (ICD-9 155.0) and treated with any locoregional therapy from 1998 to 2002 in public hospitals of Campania, southern Italy, were potentially eligible. Potential patients were retrieved from the Discharge Information System of the Regional Health Service; eligibility criteria were subsequently checked by perusing clinical records. Child-Pugh score C, presence of portal vein thrombosis, massive tumour morphology and liver involvement greater than 50% were exclusion criteria. Time interval was chosen “a priori” to allow an adequate followup.
The study protocol was approved by the ethic committees of all the participating Institutions.
Overall survival (OS) was the unique outcome measure and was defined as the time from the date of the first local intervention until death for any cause or until date of last followup. Date of death was ascertained by the administrative registry offices of patients’ towns of residence.
Baseline demographic, clinical, and tumour-related variables were derived from clinical records. The CLIP prognostic score [
Three main comparisons were planned, RFA versus PEI, surgery versus RFA or PEI, TACE/TAE versus RFA or PEI.
To minimize biases related to nonrandom assignment we used the propensity score method [
For each comparison the primary multivariable analysis was performed by a Cox proportional hazard model with compared treatments and propensity score as covariates, stratified by the number of missing values in the CLIP score components. Propensity score was estimated for each comparison by a logistic regression model that included, as covariates, age, sex, CLIP prognostic score, and number of missing components of the CLIP score [
As a sensitivity analysis, further statistical models were performed to assess the consistency of results [
Unadjusted cumulative survival curves were depicted by Kaplan-Meier (K-M) method and compared by the Mantel-Haenszel test (MH) and Peto and Peto modification of the Wilcoxon rank sum test (WPP). The two tests give different weights to events, the second one giving more weight to earlier events.
Since guidelines [
All analyses were performed with R software, version 2.9.1 (Development Core Team. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing. 2009).
Overall 441 HCC patients discharged from January 1998 and December 2002 were eligible. Sixteen cases were excluded because of lack of any follow-up information, thus the final study sample involved 425 subjects. Baseline characteristics of the 425 patients are reported in Table
Baseline characteristics of the study patients by treatment. Data are reported as absolute numbers (percentages), but for age and AFP.
Variable | Total | Surgery | PEI° | RFA° | TAE/TACE | |
---|---|---|---|---|---|---|
1998 | 33 (8%) | 4 (12%) | 23 (9%) | 2 (4%) | 4 (5%) | 0 (0%) |
1999 | 83 (20%) | 5 (15%) | 55 (21%) | 9 (18%) | 14 (18%) | 0 (0%) |
2000 | 106 (25%) | 12 (35%) | 59 (23%) | 9 (18%) | 26 (32%) | 1 (13%) |
2001 | 112 (26%) | 7 (21%) | 68 (27%) | 16 (32%) | 21 (26%) | 1 (13%) |
2002 | 91 (21%) | 6 (18%) | 51 (20%) | 14 (28%) | 15 (19%) | 6 (75%) |
Male gender | 327 (77%) | 30 (88%) | 188 (73%) | 40 (80%) | 65 (81%) | 7 (88%) |
Age | 67 (8) | 62 (7) | 68 (7) | 67 (8) | 64 (8) | 68 (7) |
Histology | 195 (46%) | 23 (68%) | 125 (49%) | 13 (26%) | 32 (40%) | 3 (38%) |
Instrumental + AFP > 200 | 51 (12%) | 3 (9%) | 28 (11%) | 9 (18%) | 12 (15%) | 0 (0%) |
Instrumental only | 179 (42%) | 8 (24%) | 103 (40%) | 28 (56%) | 36 (45%) | 5 (63%) |
Ultrasonography | 187 (44%) | 11 (32%) | 123 (48%) | 21 (42%) | 27 (34%) | 6 (75%) |
NMR | 13 (3%) | 4 (12%) | 4 (2%) | 5 (10%) | 0 (0%) | 0 (0%) |
CT | 178 (42%) | 14 (41%) | 96 (38%) | 20 (40%) | 48 (60%) | 2 (25%) |
Missing | 47 (11%) | 5 (15%) | 33 (13%) | 4 (8%) | 5 (6%) | 0 (0%) |
Liver cirrhosis | 414 (97%) | 32 (94%) | 250 (98%) | 49 (98%) | 78 (98%) | 8 (100%) |
Chronic Hepatitis | 11 (3%) | 2 (6%) | 6 (2%) | 1 (2%) | 2 (2%) | 0 (0%) |
Viral | 366 (86%) | 32 (94%) | 214 (83%) | 46 (92%) | 71 (89%) | 6 (75%) |
Nonviral | 10 (2%) | 0 (0%) | 8 (3%) | 0 (0%) | 2 (2%) | 0 (0%) |
Missing | 49 (12%) | 2 (6%) | 34 (13%) | 4 (8%) | 7 (9%) | 2 (25%) |
HCV | 324 (76%) | 24 (71%) | 197 (77%) | 43 (86%) | 56 (70%) | 7 (88%) |
HBV | 59 (14%) | 9 (26%) | 21 (8%) | 11 (22%) | 18 (22%) | 1 (13%) |
A | 200 (47%) | 22 (65%) | 105 (41%) | 26 (52%) | 42 (52%) | 7 (88%) |
B | 137 (32%) | 8 (24%) | 79 (31%) | 20 (40%) | 31 (39%) | 0 (0%) |
Missing | 88 (21%) | 4 (12%) | 72 (28%) | 4 (8%) | 7 (9%) | 1 (12%) |
AFP | 27 (7–156) | 12 (3–146) | 28 (8–127) | 34 (9–183) | 31 (7–334) | 14 (5–27) |
<4 | 305 (72%) | 25 (74%) | 189 (74%) | 38 (76%) | 49 (61%) | 5 (62%) |
≥4 | 12 (3%) | 0 (0%) | 3 (1%) | 1 (2%) | 8 (10%) | 0 (0%) |
Missing | 108 (25%) | 9 (26%) | 64 (25%) | 11 (22%) | 23 (29%) | 3 (38%) |
≤3 | 207 (49%) | 13 (38%) | 143 (56%) | 24 (48%) | 23 (29%) | 5 (62%) |
3–5 | 90 (21%) | 9 (26%) | 43 (17%) | 11 (22%) | 28 (35%) | 0 (0%) |
>5 | 39 (9%) | 4 (12%) | 12 (5%) | 7 (14%) | 15 (19%) | 1 (12%) |
Missing | 89 (21%) | 8 (24%) | 58 (23%) | 8 (16%) | 14 (18%) | 2 (25%) |
Single nodule | 204 (48%) | 18 (53%) | 132 (52%) | 23 (46%) | 26 (32%) | 5 (62%) |
Multiple nodules | 175 (41%) | 10 (29%) | 93 (36%) | 24 (48%) | 48 (60%) | 3 (38%) |
Missing | 46 (11%) | 6 (18%) | 31 (12%) | 3 (6%) | 6 (8%) | 0 (0%) |
0 | 76 (18%) | 9 (26%) | 43 (17%) | 10 (20%) | 12 (15%) | 2 (25%) |
1 | 111 (26%) | 10 (29%) | 65 (25%) | 13 (26%) | 23 (29%) | 1 (12%) |
2 | 59 (14%) | 3 (9%) | 29 (11%) | 9 (18%) | 19 (24%) | 1 (12%) |
3 | 14 (3%) | 0 (0%) | 6 (2%) | 3 (6%) | 5 (6%) | 0 (0%) |
>3 | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
Missing | 165 (39%) | 12 (35%) | 113 (44%) | 15 (30%) | 21 (26%) | 4 (50%) |
°Including three subjects who received both RFA and PEI;
Kaplan-Meier cumulative survival curves for the study treatments.
In Table
Effectiveness of locoregional treatment on overall survival in Cox proportional hazard model adjusted by propensity score.
Model | HR (95% CI) | |
---|---|---|
RFA versus PEI | 1.11 (0.79–1.57) | 0.53 |
Surgery versus RFA/PEI | 0.95 (0.64–1.41) | 0.79 |
TAE/TACE versus RFA/PEI | 0.88 (0.66–1.17) | 0.38 |
PEI: percutaneous ethanol injection, RFA radiofrequency ablation, TACE/TAE: transarterial embolization with (TACE) or without (TAE) chemotherapy.
Hazard ratio (HR) of RFA versus PEI was equal to 1.11 (95% C.I. 0.79 to 1.57,
HR of surgery versus the two percutaneous ablation therapies combined was equal to 0.95 (95% C.I. 0.64 to 1.41,
HR of TACE/TAE versus the two percutaneous ablation therapies combined was equal to 0.88 (95% C.I. 0.66 to 1.17,
Superimposable results were found for all comparisons at sensitivity analyses, where other adjustment modalities were applied (Table
Effectiveness of locoregional treatment on overall survival in Cox proportional hazard model adjusted by propensity score. Sensitivity analysis.
Model | HR (95% CI) | |
---|---|---|
Adjustment by propensity score ( | ||
Linear | 1.11 (0.79–1.57) | 0.53 |
Cubic spline | 1.09 (0.77–1.54) | 0.63 |
Stratified (quintiles) | 1.11 (0.78–1.58) | 0.56 |
Inverse probability weighting | 1.13 (0.82–1.57) | 0.46 |
Adjustment by prognostic covariates ( | 1.21 (0.87–1.71) | 0.25 |
Adjustment by propensity score ( | ||
Linear | 0.95 (0.64–1.41) | 0.79 |
Cubic spline | 0.95 (0.64–1.41) | 0.81 |
Stratified (quintiles) | 0.95 (0.61–1.48) | 0.82 |
Inverse probability weighting | 0.80 (0.52–1.24) | 0.32 |
Adjustment by prognostic covariates ( | 0.96 (0.64–1.42) | 0.82 |
Adjustment by propensity score ( | ||
Linear | 0.88 (0.66–1.17) | 0.38 |
Cubic spline | 0.89 (0.67–1.18) | 0.41 |
Stratified (quintiles) | 0.86 (0.65–1.15) | 0.32 |
Inverse probability weighting | 0.98 (0.73–1.32) | 0.90 |
Adjustment by prognostic covariates ( | 0.83 (0.63–1.10) | 0.20 |
PEI: percutaneous ethanol injection, RFA: radiofrequency ablation, TACE/TAE: transarterial embolization with (TACE) or without (TAE) chemotherapy.
Results of univariate analyses in predefined subgroups of subjects for the three comparisons are reported in Figure
Univariate comparisons of RFA versus PEI (left panel), surgical resection versus RFA/PEI (middle panel) and TACE/TAE versus RFA/PEI (right panel) within major patient subgroups. The area of each square is proportional to the size of the subgroup; horizontal lines depict 95% confidence intervals of the hazard ratio estimates.
This observational study in a clinical practice setting did not find survival differences between local treatments in any of the study comparisons. Clearly, robust evidence of treatment efficacy may only result from adequately powered randomized trials and observational studies may be flawed by several shortcomings. However, our findings add a notable piece of information to the literature of locoregional treatments for HCC, where only small clinical trials, if any, are available and are usually performed in specialized reference centers on well-selected patients.
In this study we addressed the potential biases of observational studies in several ways. First, we pursued a population-based approach, identifying the reservoir of potentially eligible patients from an independent source (the Discharge Information System of the Campania Regional Health Service), thus reducing the risk of selection bias. In addition we chose survival as the unique endpoint of the study, as recommended when effectiveness between therapies is assessed [
A major strength of our study is the length of followup with a large number of deaths observed (91% of the whole sample), that allowed a complete picture of the survival experience of the study cohort. To our knowledge, our cohort is the largest reported in the literature for this kind of study, after the one of Arii et al. who used a population-based approach starting from a nationwide survey in Japan [
We adjusted for missing information in multivariable analyses, but we acknowledge that missing data might partially affect our findings. Furthermore we only assessed first-line local treatments, since information on successive treatments was largely unreliable.
The major and unexpected finding of our results was the lack of significant differences even in univariate analyses, where we expected survival differences at least as a consequence of indication bias. Actually patients’ baseline characteristics overlapped substantially among treatments, despite the careful selection recommended by the international guidelines [
Although our results may appear surprising, they mirror some uncertainties of the literature results. Two meta-analyses [
Surgery has been compared to percutaneous ablation in three small randomized trials [
To our knowledge TACE/TAE alone have never been compared with other locoregional treatments since guidelines consider TACE/TAE as restricted to ‘nonsurgical HCC that are also ineligible for percutaneous ablation [
In conclusion, although our approach does not allow definitive statements, our results show that, in a real-world setting, uncertainties in the choice and in the outcome of local treatments of HCC are still present. Educational projects and population-based observational studies, supported by well-planned RCTs, are still needed to define the relative effectiveness of locoregional treatments.
Cardarelli Hospital, Napoli (G. Di Costanzo, F. Calise, F. Paradiso, L. Staiano); National Cancer Institute, Napoli (F. Perrone, M. Di Maio, G. Olivieri, V. Molese), Incurabili Hospital, Napoli (M. Visconti, A. Salvio, L. De Paola); Pellegrini Hospital, Napoli (A. Guaragna); Ascalesi Hospital, Napoli (G. Marone); Loreto nuovo Hospital, Napoli (W. Longanella); Second University of Napoli: Infectious diseases (GB Gaeta, M. Stanzione, G. Stornaiuolo), Internal medicine (L. Rinaldi); Gastroenterology (I. De Sio); Surgery (G. Galizia); S. Sebastiano Hospital, Caserta (G. Piai, A. Annunziata, T. Sgueglia); Moscati Hospital, Avellino (V. Castaldo); Rummo Hospital, Benevento (B. Daniele, R. Lanzetta); District Hospital, Aversa (B. Russo).
All the authors declare no conflict of interests for this paper.
This study was supported by AIRC (Associazione Italiana per la Ricerca sul Cancro). AIRC is a nonprofit charity, that supported the study without any intervention on it. S. Signoriello and A. Annunziata contributed equally to this work.