Importance
Hepatocellular carcinoma (HCC) has the second-highest cancer-related mortality rate in the world because most patients are diagnosed at an intermediate to advanced stage when surgery is not suitable. Transcatheter arterial chemoembolization (TACE) is currently considered a first-line therapy for unresectable HCC. However, advancements in radiotherapy (RT) have resulted in some studies identifying a significant therapeutic benefit of TACE plus RT for unresectable HCC compared with TACE alone.
Objective
To evaluate the efficacy and safety of TACE plus RT compared with TACE alone for unresectable HCC using meta-analytical techniques.
Data Sources
A search of Medline, EMBASE, PubMed, Cochrane, and Google Scholar databases was done from inception to January 14, 2015.
Study Selection
Published trials that included a treatment group receiving TACE plus RT and a control group receiving TACE alone with data for at least 1-year survival or tumor response were included.
Data Extraction and Synthesis
Pooled odds ratios (ORs) and 95% CIs were calculated for the effect of TACE plus RT vs TACE alone on survival, tumor response, and adverse events using a random effects model. Subgroup analyses of study design, anticancer drug, RT type, embolization type, presence of portal venous tumor thrombosis (PVTT), and time between treatments with TACE and RT were performed.
Main Outcomes and Measures
Survival, tumor response, adverse events, study design, anticancer drug, RT type, embolization type, presence of PVTT, and time between TACE and RT.
Results
There were 25 trials (11 RCTs) involving 2577 patients. Patients receiving TACE plus RT showed significantly better 1-year survival (OR, 1.36 [95% CI, 1.19-1.54]) and complete response (clearance of the lesion after treatment) (OR, 2.73 [95% CI, 1.95-3.81]) compared with TACE alone. The survival benefit progressively increased for 2-, 3-, 4-, and 5-year survival (respectively: OR, 1.55 [95% CI, 1.31-1.85]; OR, 1.91 [95% CI, 1.55-2.35]; OR, 3.01 [95% CI, 1.38-6.55]; OR, 3.98 [95% CI, 1.86-8.51]). There was an increased incidence of gastroduodenal ulcers and elevated levels of alanine transaminase and total bilirubin in patients receiving TACE plus RT compared with those receiving TACE alone. Subgroup analyses showed nonsignificant trends in which survival was greater for TACE plus RT in patients with PVTT compared with those without PVTT.
Conclusions and Relevance
TACE plus RT was more therapeutically beneficial than TACE alone for treating HCC, and should be recommended for suitable patients with unresectable HCC.
Worldwide, hepatocellular carcinoma (HCC) is the sixth most common cancer in the world, with 782 000 new cases diagnosed in 2012.1,2Quiz Ref ID It ranks second in the world as a cause of cancer-related mortality.2 In countries where HCC surveillance is not undertaken, HCC has a fulminant course, low resectability rate, high postresection recurrence rate, and a poor response to conservative treatment.3
Most HCCs are diagnosed at an intermediate to advanced stage, when treatment options such as surgical resection, liver transplantation, and percutaneous ablation are not suitable (stages B and C of the Barcelona Clinic Liver Cancer [BCLC] system).4 Transcatheter arterial chemoembolization (TACE) is currently considered as a first-line therapy for patients with HCC, BCLC stage B, or those with an excellent liver function and multinodular asymptomatic tumors without macroscopic vascular invasion or extrahepatic spread.5 Without treatment, the natural median survival for patients with intermediate-stage (BCLC stage B) HCC is 16 months. The median survival for those receiving TACE is 20 months.6 Two previous meta-analyses7,8 found that chemoembolization significantly improves 2-year survival compared with nonactive treatment; however, the magnitude of the benefit is relatively small.
In the past decade, an increasing number of studies have identified a significant therapeutic benefit of radiotherapy (RT) in addition to TACE for UHCC.9,10 Previously, the use of RT for HCC has been limited by the risk of radiation-induced liver disease (RILD) and the low tolerance of the whole liver to RT.11 With advances such as 3-dimensional (3-D) conformal RT (3-D CRT) and stereotactic RT (SRT), higher radiation doses can be directed to the tumor while sparing the non–tumor-bearing liver and surrounding organs from substantial radiation.12,13
Although previous evidence has indicated that TACE plus RT is more effective than TACE alone for treating patients with intermediate-stage HCC (stage B BCLC) as well as in patients with portal vein tumor thrombosis (PVTT),14-16 it remains unclear whether the evidence is scientifically rigorous enough to recommend its routine use. The purpose of this meta-analysis is to evaluate the efficacy and safety of TACE plus RT vs TACE alone from the results of published randomized and nonrandomized clinical trials (RCTs and non-RCTs, respectively), and to perform subgroup analysis depending on study design, anticancer drug, RT type, embolization type, presence of PVTT, and time between treatments with TACE and RT.
Box Section Ref IDAt a Glance
We evaluated the efficacy and safety of transcatheter arterial chemoembolization (TACE) plus radiotherapy (RT) compared with TACE alone for unresectable hepatocellular carcinoma via a meta-analysis.
TACE plus RT showed significantly better 1-year survival (odds ratio [OR], 1.36 [95% CI, 1.19-1.54]) and complete response (OR, 2.73 [95% CI, 1.95-3.81]) compared with TACE alone.
The survival benefit progressively increased for 2-, 3-, 4-, and 5-year survival (respectively: OR, 1.55 [95% CI, 1.31-1.85]; OR, 1.91 [95% CI, 1.55-2.35]; OR, 3.01 [95% CI, 1.38-6.55]; OR, 3.98 [95% CI, 1.86-8.51]).
There was an increased incidence of gastroduodenal ulcers and elevated levels of alanine transaminase and total bilirubin in patients receiving TACE plus RT compared with those receiving TACE alone.
We followed the PRISMA guidelines.17 A systematic search of MEDLINE, PubMed, EMBASE, Google Scholar, and Cochrane Library from inception through to January 14, 2015, was performed. The search used the terms “chemoembolization” OR “radiotherapy,” which were searched as text words and as exploded medical subject headings where possible. The reference lists of relevant articles were also searched for appropriate studies. There were no language restrictions, and a search for unpublished literature was not performed.
Acceptable publications complied with the following criteria: (1) HCC confirmed pathologically or diagnosed by computed tomography (CT); (2) trials described as RCTs or non-RCTs; (3) published trials that included a treatment group receiving TACE plus RT and a control group receiving TACE alone; and (4) data on at least 1-year survival or tumor response for the calculation of the odds ratio (OR) at a 95% CI. Abstracts, letters, case reports, and studies that lacked control groups were excluded. In treatment centers with multiple publications, the most recent and/or largest publication was included.
Data extraction was performed using a standardized form, collecting information on the (1) study, patient, and tumor characteristics; (2) treatment; and (3) outcomes such as survival, tumor response, and adverse events. Survival included 1- to 5-year survival rates, which were either reported in the trials or derived from the survival curves. Tumor response was evaluated by the change in tumor size on abdominal CT and magnetic resonance imaging (MRI) before and after treatment. Tumor response rates would be recorded according to the modified Response Evaluation Criteria in Solid Tumours (RECIST) guidelines for HCC18 (CR, complete response [complete clearance of the lesion after treatment]; PR, partial response [at least a 30% decrease in the sum of diameters of viable target lesions]; PD, progressive disease [an increase of at least 20% in the sum of the diameters of viable target lesions, taking as reference the smallest sum of the diameters of viable enhancing target lesions recorded since treatment]; NR, no response; SD, all other variations). The response rate was the sum of CR and PR.
The quality of each included RCT was assessed in accordance with the Cochrane format19 using a grading scheme for each of 4 main aspects: (1) quality of randomization, (2) quality of allocation concealment, (3) quality of blinding, and (4) quality of the description of withdrawals and dropouts. These 4 were further graded as (A) adequate, with correct procedures; (B) unclear, without a description of methods; or (C) inadequate procedures, methods, or information. The overall quality of the studies would then be assessed and classified into 3 groups as follows: (A) low risk of bias for studies with A grades for all items, (B) moderate risk of bias for studies with 1 or more B grades, or (C) high risk of bias for studies with 1 or more C grades. Quality of non-RCTs studies was not assessed.
Pooled ORs and 95% CIs were calculated for the effect of TACE plus RT vs TACE alone on survival, tumor response, and adverse events using a random effects model.19 We quantified the degree of heterogeneity using the I2 statistic, which represents the percentage of the total variability across studies that is due to heterogeneity. I2 values of 25%, 50%, and 75% corresponded to low, moderate, and high degrees of heterogeneity, respectively.20 We quantified publication bias using the Egger regression model,21 with the effect of bias assessed using the fail-safe number method. The fail-safe number was the number of studies that we would need to have missed for our observed result to be nullified to statistical nonsignificance at the P < .05 level. Publication bias is generally regarded as a concern if the fail-safe number is less than 5n +10, with n being the number of studies included in the meta-analysis.22 All analyses were performed with Comprehensive Meta-analysis software (version 2.0 for Windows; Biostat).
A total of 12 471 studies were identified in our initial broad search. A large number of studies were excluded because they were abstracts, animal studies, laboratory projects, or case studies. After carefully reading titles and abstracts, 29 articles were selected for possible inclusion in the review. Following reading the full text, 7 were excluded owing to duplication or because the objective did not satisfy the inclusion criteria. Manual search of the bibliographies found 2 additional articles. Ultimately, 25 trials (2577 patients) met our inclusion criteria, with 11 RCTs23-33 and 14 non-RCTs9,10,34-40 (eFigure 1 in the Supplement). The study designs were collected, and quality was assessed.
The percentage of studies that described the mean age of their patients was 68% (17 of 25); severity of liver disease by Child-Pugh score, 76% (19 of 25); nodule size, 72% (18 of 25); hepatitis serology findings, 28% (7 of 25); and clinical stage, 60% (15 of 25). Some trials involved patients with clinical stage III or IV (8 of 25 [32%]), and some included patients with PVTT (18 of 25 [72%]). Only 1 trial37 had 1 patient with Child-Pugh cirrhosis (1 of 25 [4%]); 91.7% (22 of 24) used 2 or more anticancer drugs, and 29,35 (2 of 24 [8.3%]) used only 1 anticancer agent. The most common anticancer drugs used were cisplatin (19 of 25 [76%]), fluorouracil (15 of 25 [60%]), mitomycin-C (14 of 25 [56%]), and adriamycin (14 of 25 [56%]). Usually, lipiodol was mixed with anticancer drugs at a uniform dosage or a dosage calculated according to tumor size before the procedure. The dosage of lipiodol ranged from 1 to 30 mL. Most used lipiodol with either gelatin sponge or polyvinyl alcohol for embolization (16 of 25 [64%]), while others used lipiodol alone for embolization (7 of 25 [28%]). The number of TACE courses ranged from 1 to 8, and the intervals between sessions of TACE ranged from 4 to 8 weeks. These characteristics are listed in the Table and eTable 1 in the Supplement.
Radiotherapy techniques that were used included the moving strip (MS) technique for whole-liver irradiation,23,27,30,31,33,37,41,42 3-D CRT,9,10,24-26,29,32,34-36,38-40,43,44 and SRT.28,45 Three-dimensional CRT used CT or MRI to delineate the gross tumor volume. The clinical target volume included the gross tumor volume plus a 1.0- to 1.5-cm margin within the liver. The planning target volume included the clinical target volume plus a 0.5- to 2.5-cm margin. As for fractional schedule, there were 7 trials25,26,28,29,43-45 that adopted hypofraction RT, 159,10,23,24,31,32,34-42 that adopted conventional fractionated RT, and 327,30,33 that adopted hyperfractionation accelerated RT. We calculated the total dose of RT based on the biologically effective dose equivalence model, which ranged from 30.6 to 100.8 Gy. The most common use of RT was after completion of TACE, with an interval ranging from 5 to 60 days after RT. Two studies23,42 used RT sandwiched between TACE procedures, and 1 study36 used RT before, between, and after TACE in different patients. These characteristics are listed in eTable 2 in the Supplement.
Methodological Quality of RCTs
In terms of quality, all 11 RCTs were graded B. Only 1 trial30 was described with the term “double-blinding.” Ten trials23-29,31-33 stated that randomization had been used, but none reported that the generation of a random allocation sequence in detail. Only 1 trial23 provided information on allocation concealment by the envelope method. No trials reported prior to the sample size estimation. Two trials performed intention-to-treat analysis.27,30 In 4 reports,23,28,31,32 dropout rates were stated, but no explanations were given (eTable 3 in the Supplement).
Median survival and 1- to 5-year survival.
The pooled median survival for TACE plus RT was significantly better than for TACE alone (22.7 months vs 13.5 months; P < .001, respectively). This was pooled from 22 studies, with 1032 patients receiving TACE plus RT and 1354 receiving TACE only (Figure 1A). The 1-, 2-, 3-, 4-, and 5-year survival rates were reported in 25, 20, 20, 3, and 4 trials, respectively. Meta-analysis showed that TACE plus RT seemed to significantly increase 1-year survival compared with TACE alone (OR, 1.36 [95% CI, 1.19-1.54]). The benefit of TACE plus RT continuously increased for 2-, 3-, 4-, and 5-year survival (OR, 1.55 [95% CI, 1.31-1.85]; OR, 1.91 [95% CI, 1.55-2.35]; OR, 3.01 [95% CI, 1.38-6.55]; OR, 3.98 [95% CI, 1.89-8.51], respectively) (Figure 1A and Table). The pooled 1- to 5-year survival rates across all studies are summarized in eFigure 2 in the Supplement.
Treatment with TACE plus RT was identified as an independent predictor of mortality in 2 studies (adjusted HR, 0.38 [95% CI, 0.20-0.71]37 and adjusted HR, 0.48; P < .001; regression coefficient, −0.7335).
Complete response, PR, NR, and PD were reported in 16, 16, 15, and 14 studies, respectively. Meta-analysis showed that TACE plus RT seemed to significantly improve CR and PR compared with TACE alone (OR, 2.73 [95% CI, 1.95-3.81]; OR, 1.47 [95% CI, 1.23-1.75], respectively). TACE plus RT seemed to be significantly associated with lower rates of NR and PD compared with TACE alone (OR, 0.56 [95% CI, 0.44-0.71]; OR, 0.43 [95% CI, 0.31-0.60], respectively) (Figure 1B and Table).
Treatment-Associated Complications
One study36 reported 1 death from hepatic failure in the TACE-only group. Another study44 reported 4 treatment-related deaths in the combination group owing to RILD.
Two trials9,39 were identified with outcome measurements of gastroduodenal ulcers. Quiz Ref IDThe pooled analysis showed that compared with TACE alone, TACE plus RT significantly increased gastroduodenal ulcers (OR, 12.80 [95% CI, 1.57-104.33]) (Figure 2).
Alanine aminotransferase level increase.
Three trials24,29,39 were identified with outcome measurements of elevated levels of alanine aminotransferase (ALT). The pooled analysis showed that compared with TACE alone, TACE plus RT significantly increased the elevation of ALT level (OR, 2.46 [95% CI, 1.30-4.65]) (Figure 2).
Total bilirubin level increase.
Three trials24,29,45 were identified with outcome measurements of elevated levels of total bilirubin (TB). The pooled analysis showed that compared with TACE alone, TACE plus RT significantly increased the incidence of elevated levels of total bilirubin (OR, 2.16 [95% CI, 1.05-4.45]) (Figure 2).
Decline of leukocyte count.
Nine trials9,24,26,29,33,34,39,43,45 were identified with outcome measurements of leukocyte count (LC) decline. The pooled analysis showed that compared with TACE alone, TACE plus RT did not significantly cause leukocyte count decline (OR 1.22 [95% CI, 0.91-1.62]) (Figure 2).
Six trials24,26,33,35,39,42 were identified with outcome measurements of nausea and/or vomiting. The pooled analysis showed that compared with TACE alone, TACE plus RT did not significantly increase the incidence of nausea and/or vomiting (OR, 1.03 [95% CI, 0.74-1.44]) (Figure 2).
Two trials24,45 were identified with outcome measurements of thrombocytopenia. The pooled analysis showed that compared with TACE alone, TACE plus RT did not significantly increase the incidence of thrombocytopenia (OR, 0.81 [95% CI, 0.38-1.72]) (Figure 2).
Four trials27,33,34,42 were identified with outcome measurements of fever. The pooled analysis showed that compared with TACE alone, TACE plus RT did not significantly increase the incidence of fever (OR, 1.13 [95% CI, 0.78-1.65]) (Figure 2).
Esophagitis or gastroduodenitis.
Four trials9,10,35,43 were identified with outcome measurements of esophagitis or gastroduodenitis. The pooled analysis showed that compared with TACE alone, TACE plus RT did not significantly increase the incidence of esophagitis or gastroduodenitis (OR, 1.98 [95% CI, 0.62-6.35]) (Figure 2).
There was no heterogeneity in 1- to 5-year survival or tumor response between the studies (P = .53-.99 for survival; P = .64-.86 for tumor responses).
Assessment of publication bias using the Egger regression model showed that publication bias was present for 1-year survival (P = .02), 3-year survival (P < .001), and CR (P < .001). No publication bias was present for 2-year survival (P = .12), 5-year survival (P = .03), PR (P = .92), NR (P = .72), or PD (P = .24).
Subgroup analyses showed that patients who received TACE plus RT had significantly better 1-, 2- and 3-year survival rates than those who received TACE alone in both patients with and those without PVTT.
Studies that included patients with PVTT had a increased 1-, 2-, and 3-year survival benefit for TACE plus RT over TACE alone than studies that did not include patients with PVTT; however, this trend was not significant. Despite the improvement in survival, there was a trend for patients with PVTT to have a poorer tumor response rates and CR, and increased tumor NR and PD compared with those without PVTT (Table).
RT Technique: 3-D CRT, MS RT, and SRT.
Subgroup analyses showed that patients receiving TACE plus RT had significantly better 1-, 2-, 3-, and 5-year survival rates than those receiving TACE alone when 3-D CRT and MS RT was used (see Table for P values). However, this comparison was nonsignificant for SRT. Comparing 3-D CRT and MS RT, there was a nonsignificant trend for MS RT to be associated with improved 1-, 2-, 3-, and 5-year survival rates. There were better response rates, lower NR, and lower PD in the 3-D CRT, SRT, and MS RT groups; however, it this was significant only for 3-D CRT and SRT. A comparison of 3-D CRT and SRT showed a nonsignificant trend for 3-D CRT to have a better response rate; however, SRT showed less NR and PD (Table).
Study type: RCTs and non-RCTs.
Subgroup analyses showed that those receiving TACE plus RT had significantly better 1-, 2-, 3-, and 5-year survival and tumor response than those receiving TACE alone in both RCTs and non-RCTs (Table).
Anticancer agent: fluorouracil, adriamycin, mitomycin-C.
Subgroup analyses showed that patients receiving TACE plus RT had significantly better 1- to 3-year survival than TACE alone in both patients receiving fluorouracil and those not receiving fluorouracil. Similar findings were found with adriamycin and mitomycin-C. There was a nonsignificant trend for patients receiving fluorouracil having improved 1- to 3-year survival rates as well as NR than for patients not receiving fluorouracil. Despite the improvement in survival, there was a nonsignificant trend for patients receiving fluorouracil to have a poorer tumor response rates and CR, and increased tumor PD compared with those not receiving fluorouracil. Similar findings were found with adriamycin. However, there was a nonsignificant trend for patients receiving mitomycin-C to have a decreased 1-, 2-, and 3-year survival rates; decreased response rates; and CR and increased NR and PD than patients not receiving mitomycin-C (eTable 4 in the Supplement).
Embolizing agent: lipidol alone vs others with or without lipiodol.
Subgroup analyses showed that patients receiving TACE plus RT had significantly better 1-, 2-, 3-, and 5-year survival than those receiving only TACE in those who had received embolizing agents other than lipiodol alone. In comparison, for those received lipiodol alone, significance was only seen for 1- and 5-year survival (eTable 4 in the Supplement).
TACE-RT Interval: 28 days or more vs less than 28 days.
For both studies, in patients who had received RT less than 28 days or 28 days or more after completion of TACE, TACE plus RT was significantly more effective than TACE alone for 1-year survival, but was not significant for 2-year survival. In both studies, in patients who had RT less than 28 days or 28 days or more after completion of TACE, TACE plus RT had significantly better response rates and CR and less NR than TACE alone. TACE performed less than 28 days before RT was associated with significantly less NR than TACE alone, while TACE performed 28 days or more before RT was not significantly associated with better NR than TACE alone. There was a nonsignificant trend for patients who had RT 28 days or more after TACE to have a better 1-year survival rates, response rates, and CR compared with patients who had RT less than 28 days after TACE (Table).
Quiz Ref IDThis meta-analysis provides evidence that TACE plus RT compared with TACE alone significantly improved 1-, 2-, 3-, 4-, and 5-year survival as well as tumor CR and PR in patients with UHCC. In regard to adverse events, we found that compared with TACE alone, TACE plus RT was associated with a greater incidence of gastroduodenal ulcers and elevation of ALA and total bilirubin levels while having similar frequencies of nausea and/or vomiting, thrombocytopenia, and fever. Subgroup analyses showed nonsignificant trends in which survival was greater for TACE plus RT in patients with PVTT compared with those without PVTT, and MS RT rather than 3-D CRT and SRT. Quiz Ref IDSlight or no differences were seen between study types, embolization type, interval between TACE and RT, or types of anticancer drugs used.
Although small volumes of liver tissue are able to tolerate high doses of radiation without serious hepatic problems,46 RT for HCC has traditionally not been used because older techniques have not been able to adequately localize the radiation to the tumor.47 However, recent improvements in RT have allowed increased intratumor radiation and decreased radiation to the adjacent normal liver and organs, thereby reducing the rate of adverse events such as RILD.48 Numerous studies have published long-term outcome benefits of using RT plus TACE in treating UHCC. We found 3 ways of combining TACE with RT in our included trials: RT before TACE, RT sandwiched between TACE treatments, or RT following TACE. Most of the studies used RT after TACE (22 of 25 [88%]). Analysis of the 2 studies23,42 in which patients received RT sandwiched between TACE treatments showed survival and tumor response rates similar to rates of those that received RT after TACE.
We speculate that the improvement of survival and tumor response rates from RT following or sandwiched between TACE treatments compared with TACE alone is due to the following reasons: (1) RT can kill residual cancer cells after TACE, especially those at the tumor periphery that remain viable through the blood supply from the collateral circulation or recanalization of the embolized artery by the portal vein11; (2) TACE damages large numbers of cancer cells, which promotes the residual cells from a nonproliferative phase into cell proliferation, and thus, become more radiosensitive49; (3) TACE decreases the tumor volume, which in turn reduces the radiation field and adverse events50; (4) retention of chemotherapeutic agents from embolization in liver tumor cells has a radiosensitizing effect and accelerates tumor necrosis51; (5) RT can increase tumor response for those tumors with little blood supply and poor filling of lipiodol emulsion; and (6) RT performed after TACE extends the tumor retention of lipiodol and anticancer agents, which avoids the need for repeated TACE.34
There is considerable interest at present in radioembolization with yttrium Y 90 and other isotopes, which has been proposed as a less toxic, less invasive alternative to TACE. Long-term survival with yttrium remains uncertain; however, preliminary studies52-54 show a survival benefit similar to that of TACE. In a 2-cohort study,52 survival was slightly better in the yttrium group compared with the TACE group (median survival, 11.5 months vs 8.5 months). However, the selection criteria indicated a significant bias toward milder disease in the yttrium group. By stratifying the model into a 3 tiers, with patients dichotomized according to bilirubin levels lower than 1.5 mg/dL, the absence of PVTT, and low α1-fetoprotein plasma levels (<25 ng/mL), an analysis of survival in clinical subgroups indicated that the 2 treatments resulted in similar survival.52 (To convert bilirubin to micromoles per liter, multiply by 17.04.) With similar survival rates, as well as substantially less cost, TACE remains preferred over radioembolization in many treatment institutions. However, this preference may change following the release of a currently ongoing RCT55 comparing radioembolization with TACE for intermediate HCC (BCLC).
In regard to adverse events, TACE plus RT was associated with a greater incidence of gastroduodenal ulcers and elevated ALA and total bilirubin levels while having similar frequencies of nausea and/or vomiting, thrombocytopenia, and fever compared with TACE alone. These adverse effects were easily managed and treated. One study36 reported 1 death from hepatic failure in the TACE-only group. Another study44 reported 4 treatment-related deaths in the combination group owing to RILD. However, this study had a mixture of patients, of whom a majority had RT before TACE and a minority had RT after or sandwiched between TACE. The authors44 did not identify which treatment was associated with RILD. It is possible that those who developed RILD had RT before TACE because this is an uncommon treatment regime, and all the other studies that had RT after TACE did not report any RILD. Additional studies to examine the rate of adverse effects in different treatment regimens of TACE plus RT are warranted.
Another objective of this study was to determine whether TACE plus RT was effective for patients with UHCC with PVTT. This is important for 3 reasons: (1) there is currently no standard treatment for PVTT, (2) PVTT is an extremely poor prognostic condition in which the median survival time without treatment is approximately 2 months,56,57 and (3) PVTT occurs in 20% to 70% of patients intermediate HCC.58,59Quiz Ref ID Our study showed that TACE plus RT compared with TACE alone was associated with significantly better 1-, 2-, and 3-year survival rates in patients with PVTT. In addition, subgroup analysis showed that there was a nonsignificant trend in which TACE plus RT was more effective than TACE alone in patients with PVTT than in those without PVTT. Previously, numerous reports15,36,60,61 demonstrated the benefit of RT alone for PVTT, whereas TACE was associated with a theoretical risk that it could result in ischemic damage to normal liver parenchyma.62 So the question remains: is the addition of TACE doing more harm than good (by reducing the benefit of RT alone)? Recent comparative studies36,63 have shown that TACE plus RT compared with RT alone significantly improves survival for patients with UHCC with PVTT. These findings suggest that the addition of TACE to RT is therapeutically beneficial for patients with UHCC with PVTT.
Our findings should be interpreted in view of certain limitations. First, of the trials included, only 11 were RCTs. Only 1 trial was described with the term “double-blinding,” whereas the other 10 trials stated use of “randomization” and did not describe the generation of a random allocation sequence in detail. No study reported the generation of a random allocation sequence or the allocation blinding in detail. Without double-blinding, the results can produce selection bias, performance bias, and measuring bias. Second, the eligibility criteria (eg, tumor stage, Child-Pugh class, follow-up, treatment design) for inclusion of patients with HCC were not identical between the studies. This might influence the consistency of effects across these included studies and lead to between-study heterogeneity. Third, all of our studies come from the East and may not be applicable to Western practice. The etiology of HCC is likely to differ from that of the West because more cases may be due to viral hepatitis rather than alcoholic disease and fatty nonalcoholic liver disease. However, this difference may be minor owing to the rising rates of alcoholic life disease and steatosis in the East. Finally, publication bias was present for 1-year survival, 3-year survival, and CR. However, the fail-safe number of studies to prevent publication bias was more than 200, and we are confident that none of the relevant published trials were overlooked owing to the extensive screening (manual and computer) of the literature. Nonetheless, publication bias is unlikely to change the direction of our pooled estimates considering that there was similar significant correlation for 2-year survival, 5-year survival, RR, NR, and PD, which had no publication bias.
The available evidence is sufficient to conclude that (1) TACE plus RT significantly reduces survival for up to 5 years in patients with UHCC and (2) TACE plus RT is more effective than TACE alone, which suggests that the addition of RT improves patient outcomes and tumor response. Future RCTs are needed to confirm the advantageous effects of combined therapy over TACE or RT alone and to clarify the optimal radiation technique, radiation dose, and optimal interval between TACE and RT.
Corresponding Author: Guy D. Eslick, DrPH, PhD, The Whiteley-Martin Research Centre, Discipline of Surgery, The University of Sydney, Nepean Hospital, Level 3, Clinical Building, PO Box 63, Penrith, NSW 2751 Australia (guy.eslick@sydney.edu.au).
Accepted for Publication: May 22, 2015.
Published Online: July 9, 2015. doi:10.1001/jamaoncol.2015.2189.
Author Contributions: Dr Eslick had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Both authors.
Acquisition, analysis, or interpretation of data: Huo.
Drafting of the manuscript: Huo.
Critical revision of the manuscript for important intellectual content: Both authors.
Statistical analysis: Both authors.
Study supervision: Eslick.
Conflict of Interest Disclosures: None reported.
Funding/Support: Dr Huo received support from the University of Sydney Summer Research Program for a research placement of 8 weeks with Dr Eslick by reimbursing transport costs and providing facilities to undertake the research, such as Internet and a printer.
Role of the Funder/Sponsor: The University of Sydney Summer Research Program had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
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