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Serum alpha-fetoprotein response can predict prognosis in hepatocellular carcinoma patients undergoing radiofrequency ablation therapy
Clinical Radiology 67 (2012) 429e436
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Serum alpha-fetoprotein response can predict prognosis in hepatocellular carcinoma patients undergoing radiofrequency ablation therapy W.-Y. Kao a, Y.-Y. Chiou b, c, *, H.-H. Hung a, c, C.-W. Su a, c, d, **, Y.-H. Chou b, c, J.-C. Wu d, e, T.-I. Huo a, f, Y.-H. Huang a, d, W.-C. Wu a, H.-C. Lin a, c, S.-D. Lee a, c a
Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taiwan Department of Radiology, Taipei Veterans General Hospital, Taiwan c Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan d Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan e Department of Medical Research and Education, Taipei Veterans General Hospital, Taiwan f Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan b
art icl e i nformat ion Article history: Received 28 June 2011 Received in revised form 11 September 2011 Accepted 25 October 2011
AIMS: To evaluate the clinical inference of serum alpha-fetoprotein (AFP) response in hepatocellular carcinoma (HCC) patients undergoing percutaneous radiofrequency ablation (RFA). MATERIALS AND METHODS: Three hundred and thirteen previously untreated HCC patients were enrolled in the study. The optimal AFP response was defined as >20% decrease from baseline after 1 month of RFA for those with a baseline AFP level of 100 ng/ml. The impact of AFP response on prognosis was analysed and prognostic factors were assessed. RESULTS: After a median follow-up of 26.7 19.1 months, 49 patients died and 264 patients were alive. The cumulative 5 year survival rates were 75.3 and 57.4% in patients with an initial AFP of <100 ng/ml and 100 ng/ml, respectively (p ¼ 0.003). In the 58 patients with a baseline AFP of 100 ng/ml and initial completed tumour necrosis after RFA, the cumulative 5 year survival rates were 62.4 and 25.7% in optimal and non-optimal AFP responders, respectively (p ¼ 0.001). By multivariate analysis, the prothrombin time international normalized ratio >1.1 (p ¼ 0.009), nonoptimal AFP response (p ¼ 0.023), and creatinine >1.5 mg/dl (p ¼ 0.021) were independent risk factors predictive of poor overall survival. Besides, the cumulative 5 year recurrence rates were 83.4 and 100% in optimal and non-optimal AFP responders, respectively (p < 0.001). Multivariate analysis demonstrated platelet count 105/mm3 (p ¼ 0.048), tumour size >2 cm (p ¼ 0.027), and non-optimal AFP response (p < 0.001) were independent risk factors associated with tumour recurrence after RFA. CONCLUSIONS: Serum AFP response may be a useful marker for predicting prognosis in HCC patients undergoing RFA. Ó 2011 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
* Guarantor and correspondent: Y.-Y. Chiou, Division of Gastrointestinal Radiology, Department of Radiology, Taipei Veterans General Hospital, 201 Shih-Pai Road, Sec. 2, Taipei 112, Taiwan. Tel.: þ886 2 28712121x7594; fax: þ886 2 28769310. ** Guarantor and correspondent: C.-W. Su, Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, 201 Shih-Pai Road, Sec.2, Taipei 112, Taiwan. Tel.: +886 2 28712121x3971; fax: + 886 2 28739318. E-mail addresses: [email protected] (Y.-Y. Chiou), cwsu2@vghtpe. gov.tw (C.-W. Su).
Introduction Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths in the world.1e3 Surgical resection, liver transplantation, and local ablation therapies are currently recognized as potentially curative treatment modalities.4 Although resection surgery and liver
0009-9260/$ e see front matter Ó 2011 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.crad.2011.10.009
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transplantation can provide better overall survival and lower rates of recurrence after therapy, they are often unfeasible due to the shortage of liver transplantation donors or the relatively poor liver functional reserve of the patients, which makes resection surgery impossible.5 Consequently, local ablation therapies have been introduced for the management of small HCC in patients that are not eligible for liver transplantation or resection therapy. Among local ablation therapies, percutaneous radiofrequency ablation (RFA) is superior to other therapies due to fewer therapy sessions, better local tumour control, and higher survival rates.6e9 Accordingly, RFA has been widely applied in patients with small HCC in recent years.10e14 Nevertheless, patients undergoing RFA have a high incidence of recurrence after completing ablation of the primary tumour. It is estimated that the cumulative 5 year recurrence rate of patients undergoing RFA is more than 70%.11,12,14e16 To improve the long-term outcome of RFA, it is crucial to elucidate the mechanisms and risks factors associated with recurrence after RFA. The serum alpha-fetoprotein (AFP) level has been widely applied as a screening, diagnostic, and prognostic tool in HCC.16,17 However, its role in monitoring treatment response and long-term prognosis has not been fully elucidated. Recently, dynamic changes of serum AFP levels reportedly reflect responses to chemotherapy18e20 and trans-arterial chemoembolization (TACE) in intermediate or advanced HCC.21 Nevertheless, studies evaluating the impact of AFP response on the prognosis of patients with small HCC after RFA are still few.22 The aim of the present study was to evaluate the clinical implications of AFP response in HCC patients undergoing RFA.
Patients and methods Patients and follow-up The present study complied with the standards of the Declaration of Helsinki and was approved by the Institutional Review Board (IRB). This cohort study retrospectively reviewed HCC patients who were not suitable or refused to resection surgery or liver transplantation and underwent RFA in Taipei Veterans General Hospital from 1 January 2002 to 31 December 2009. The choice of RFA was decided by the patients after the physicians explained the advantage, side effects, and prognosis among the various therapy modalities, including resection surgery, liver transplantation, local ablation therapy, TACE, and chemotherapy. After review of medical chart records, 313 consecutive HCC patients who fulfilled the diagnostic criteria of HCC by the American Association for the Study of Liver Disease (AASLD consensus, 2005)4 and underwent RFA as the first treatment modality were enrolled. The inclusion criteria were tumour size <5 cm without extra-hepatic metastasis; three or fewer tumours; grade A or B ChildePugh classification of liver function; and no other major diseases that
might complicate RFA. The RFA procedure was as previously described.12 Dynamic computed tomography (CT) was undertaken 1 month after all of the tumours were ablated by RFA. Magnetic resonance imaging (MRI) was performed in patients with allergies to the CT contrast medium, renal insufficiency, or inconclusive CT diagnosis. For confirmed residual tumours, a second session of RFA was conducted. If viable tumours persisted after two RFA sessions, treatment was considered a failure. When all of the tumours had been successfully destroyed and without any residual viable tumours confirmed by CT or MRI, the patient was followed-up with testing for serum liver function tests, AFP levels, and ultrasonography every 3 months; and CT or MRI every 6 months until 30 September 2010. The start date of follow-up for tumour recurrence was the day that all of the tumours ablated by RFA were confirmed by CT or MRI. Tumour recurrence was suspected if there was an elevated serum AFP level (>20 ng/ml) or new lesion detected by surveillance ultrasonography. These were confirmed and diagnosed by dynamic CT or MRI. When recurrent tumours were diagnosed, patients were treated with the appropriate management, including repeated RFA, percutaneous ethanol injection therapy, TACE, resection surgery, liver transplantation, chemotherapy, radiotherapy, or supportive treatment.
Biochemical and serological markers Serum hepatitis B surface antigens (HBsAg) were tested using radio-immunoassay (Abbott Laboratories, North Chicago, IL, USA), and antibodies to hepatitis C virus (HCV) were measured using a second-generation enzyme immunoassay (Abbott Laboratories, North Chicago, IL). Serum liver function tests, including albumin, bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (Alk-P), gamma-glutamyltransferase (GGT), blood urea nitrogen (BUN), creatinine, and glucose levels, were measured using a systemic multi-auto-analyser (Technicon SMAC, Technicon Instruments, Tarrytown, NY, USA). Serum AFP level was measured by radio-immunoassay (Serono Diagnostic SA, Coinsin/VD, Switzerland). An optimal AFP response was defined as >20% decrease from baseline after 1 month of RFA.19,20
Statistical analysis The baseline characteristics to be evaluated with outcomes were selected by the European Association for the Study of the Liver (EASL) guidelines published in 2001.23 Pearson’s chi-square analysis or Fisher’s exact test were used to compare categorical variables. As this cohort was composed of non-normal distribution populations, the nonparametric test of the ManneWhitney U-test was used to compare continuous variables of demographic data between patients with baseline serum AFP <100 ng/ml and AFP 100 ng/ml, with successful and failed RFA treatment, and with optimal and non-optimal AFP responses after RFA,
W.-Y. Kao et al. / Clinical Radiology 67 (2012) 429e436
respectively. Cumulative recurrence rates or overall survival rates were estimated by the KaplaneMeier method and compared using the Cox’s proportional hazards model. Variables with statistical significance (p < 0.05) or proximate to it (p < 0.1) by univariate analysis underwent multivariate analysis via forward stepwise Cox’s regression model. A two-tailed p < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS 17.0 for Windows (SPSS, Chicago, IL, USA).
Results Demographics data of RFA patients The demographic characteristics of all patients are shown in Table 1. Of the 313 patients, 262 were successfully treated with one RFA session and 37 had two sessions (Fig 1), for a treatment success rate of 95.5%. The remaining 14 patients with treatment failure underwent further RFA or TACE as rescue therapies. Patients with RFA treatment failure had a significantly larger tumour size (p < 0.001) than those with complete tumour necrosis after one to two sessions of RFA therapy. Besides, 158 patients had normal baseline serum AFP levels (<20 ng/ml), 93 patients had AFP levels between 20 and 100 ng/ml, and the remaining 62 patients had an AFP level of l00 ng/ml. Demographic data between patients with initial serum AFP levels of 100 ng/ ml and those with <100 ng/ml are shown in Supplementary Material Table S1. There was a trend for patients with an initial serum AFP levels of <100 ng/ml to have a smaller
431
tumour size (p ¼ 0.066). Liver functional reserve, age, sex, and viral factors were comparable between the two groups. In the study cohort, 59 patients received anti-viral therapy after RFA, including 18 patients with lamivudine, 15 patients with entecavir, and 26 patients with pegylated interferon therapy.
Factors associated with overall survival and recurrence After median follow-up of 26.7 19.1 months, 49 patients died and 264 were still alive. The overall cumulative survival rates at 1, 2, 3, and 5 years were 96.6, 88.5, 81, and 72.3%, respectively. Stratified by the baseline serum AFP level, the overall cumulative survival rates at 1, 2, 3, and 5 years were 97.5%, 90.9, 84.3, and 75.3%, respectively, in patients with an initial AFP of <100 ng/ml, and 92.5, 75.6, 63.1, and 57.4%, respectively, in patients with a serum AFP of 100 ng/ml (p ¼ 0.003, Fig 2a). In the 299 patients with complete tumour necrosis after one to two sessions of RFA therapy confirmed by CT or MRI, 190 had tumour recurrence, with 12.3 16.4 months median time of development. The cumulative rate of recurrence at 1, 2, 3, and 5 years were 40.1, 57.7, 72.3, and 80.6%, respectively. Stratified by baseline AFP levels, the cumulative recurrence rates at 1, 2, 3, and 5 years were 37.9, 53.6, 68.9, and 78.5%, respectively, in patients with a serum AFP of <100 ng/ml and 53.6, 74.8, 87.1, and 87.1%, respectively, in patients with an AFP of 100 ng/ml (p ¼ 0.002, Fig 2b).
Table 1 Comparison of demographic data between patients with successful and failed radiofrequency ablation (RFA) treatment. Parameter
Total (n ¼ 313)
Patient demographics Age (years) (mean SD) 68.1 11.3 Sex (M/F) (%) 199/114 (63.6%/36.4%) Serum biochemistry tests and liver function testsa Albumin (g/dl) 3.9; 3.4e4.2 Total bilirubin (mg/dl) 0.8; 0.5e1.2 ALT (U/L) 51; 35.0e90.5 Creatinine (mg/dl) 1; 0.8e1.2 Alk-P(U/L) 95; 71.3e126 ICG-15R (%) 17; 9.8e29 PT-INR 1; 1e1.1 113,000; 83,500e157,000 Platelet (/mm3) ChildePugh A/B 274/38 (87.5%/12.1%) Viral factors HBsAg 134/160 (positive/negative) (44.7%/53.3%) Anti-HCV 142/155 (positive/negative) (47.2%/51.5%) Antiviral agents 59/254 (yes/no) (18.8%/81.2%) Tumour factors Tumour size (cm) 2.3; 1.6e2.9 Single/multi-nodularity (%) 263/50 (84%/16%) AFP (ng/mL) 19.6; 8e60.8 AFP 100 ng/ml (%) 251/62 (80.2%/19.8%)
Success (n ¼ 299)
Failure (n ¼ 14)
67.9 11.4 190/109 (63.5%/36.5%)
72.1 8.9 9/5 (66.7%/33.3%)
0.168 1.000
3.9; 3.4e4.2 0.8; 0.5e1.2 51.0; 32.0e92 1; 0.8e1.2 95; 76e128 17.5; 9e29 1; 1e1.1 113,000; 82,000e156,000 261/37 (87.3%/12.4%)
4.2; 3.6-4.4 0.9; 0.6e1.0 38.5; 31.5e63 1; 0.7e1.2 80; 64.5e112.5 16; 11e35.5 1; 1e1.1 110,000; 87,250e169,500 13/1 (92.7%/7.1%)
0.150 0.533 0.358 0.732 0.950 0.998 0.226 0.700 0.530
126/154 (44.1%/53.8%) 137/146 (47.7%/50.9%) 57/242 (19.1%/80.9%)
8/6 (57.1%/42.9%) 5/9 (35.7%/64.3%) 2/12 (14.3%/85.7%)
0.538
2.2; 1.6e2.9 251/48 (83.9%/16.1%) 19.9; 8e60 241/58 (80.6%/19.4%)
3.1; 2.8e3.9 12/2 (85.7%/14.3%) 10.9; 4.9e173.5 10/4 (71.4%/28.6%)
p
0.513 1.000
<0.001 1.000 0.810 0.489
M/F, male/female; ALT, alanine aminotransferase; Alk-P, alkaline phosphatase; ICG-15R, indocyanine green dye retention rate at 15 minutes; PT-INR, prothrombin time international normalized ratio; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; AFP, alpha-fetoprotein. a Continuous variables are expressed as median; 25 and 75 percentiles.
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Figure 1 Flow chart summarizing the treatment courses of the enrolled patients.
Factors associated with overall survival in patients with baseline serum AFP 100 ng/ml and successful treatment Fifty-eight patients with baseline serum AFP levels 100 ng/ml had complete tumour necrosis after one to two sessions of RFA therapy (Fig 1). There was an optimal AFP response in 46 patients, with >20% reduction in serum AFP levels from baseline after 1 month of RFA therapy. The remaining 12 patients were defined as AFP non-optimal responders. Demographic characteristics between patients with and without an optimal AFP response are compared in Table 2. Patients in the non-optimal AFP response group were older (p ¼ 0.047) and there was a higher incidence of chronic carriers of hepatitis C virus (HCV; p ¼ 0.043). Conversely, patients in the optimal AFP response group had smaller tumour sizes (p ¼ 0.011) and lower baseline serum AFP levels (p ¼ 0.046). The cumulative overall survival rates at 1, 2, 3, and 5 years were 97.5, 86.3, 70.2, and 62.4%, respectively, in patients with an optimal AFP response, and 68.5, 25.7, 25.7, and 25.7%, respectively, in AFP non-optimal responders. Overall survival rates were significantly higher in HCC patients with an optimal AFP response (p ¼ 0.001, Fig 2c). Univariate analysis indicated that the following were associated with poor overall survival: lower serum albumin levels (3.7 g/dl), lower platelet counts (<105/mm3), higher prothrombin time (PT) international normalized ratio (INR; > 1.1), non-optimal AFP response, larger tumour size (>2 cm),
and higher serum creatinine levels (>1.5 mg/dl; Supplementary Material Table S2). Older patients (age >65 years) had a trend of poor overall survival (p ¼ 0.094). By multivariate analysis, PT INR >1.1 [hazard ratio (HR) 8.243, p ¼ 0.009], non-optimal AFP response (HR 5.481, p ¼ 0.023), and creatinine >1.5 mg/dl (HR 11.195, p ¼ 0.021) were independent risk factors predictive of poor overall survival in patients with initial serum AFP levels of 100 ng/ ml and complete tumour necrosis after one to two sessions of RFA therapy (Table 3).
Factors associated with recurrence after RFA in patients with baseline serum AFP 100 ng/ml and successful treatment In this sub-cohort, the cumulative recurrence rates at 1, 2, 3, and 5 years were 43.5, 67.7, 83.4, and 83.4%, respectively, in patients with optimal AFP response and 91.7, 100, 100, and 100%, respectively, in AFP non-optimal responders. The total recurrence rates were significantly higher in patients with a non-optimal AFP response (p < 0.001, Fig 2d), all of whom developed recurrence within 2 years after RFA therapy. Multivariate analysis showed that a platelet count of 105/mm3 (HR 1.936, p¼0.048), a non-optimal AFP response (HR 4.220, p < 0.001), and tumour size >2 cm (HR 2.360, p ¼ 0.027) were independent risk factors associated with higher incidence of recurrence after RFA in patients with initial serum AFP levels 100 ng/ml and complete tumour necrosis after one to two sessions of RFA therapy (Table 3).
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Figure 2 Cumulative overall survival and recurrence rates stratified by initial serum AFP levels and AFP response. Patients with initial serum AFP levels of 100 ng/ml had (a) lower overall survival rates (p ¼ 0.003) and (b) a higher incidence of recurrence (p ¼ 0.002) than those with an initial serum AFP of <100 ng/ml. For patients with initial serum AFP levels of 100 ng/ml, those with an optimal AFP response after RFA had (c) better overall survival rates (p ¼ 0.001) and (d) lower incidences of recurrence (p < 0.001) than those with a non-optimal AFP response.
Discussion Although AFP measurements have been undertaken for the diagnosis of HCC in recent decades, serial AFP levels have not been widely applied for monitoring treatment response after RFA therapy. The results of the present study shows that patients with an adequate AFP response, defined by a decline of more than 20% 1 month after RFA therapy, have a better prognosis than those with a non-optimal response. This result is consistent with other observational studies of HCC patients receiving surgery, locoregional therapies, and systemic chemotherapy.19e22,24,25 The decline in AFP levels after therapy is likely a reflection of decreased tumour burden.26 In contrast, elevation of serum AFP levels after anti-tumour therapy also likely represents re-expansion of the tumour, either by incomplete treatment or the development of de novo new growth. Consequently, an optimal AFP response may serve as an easy, objective, and non-invasive tool to monitor the emergence of recurrence after RFA. It is recommended that serial AFP levels be checked before and 1 month after RFA for HCC patients with elevated AFP levels. According to the study conducted by Tateishi et al.,27 when baseline serum AFP levels are <100 ng/ml, most
patients show no significant change in AFP levels after RFA therapy. The present cohort also had similar findings. Moreover, Liaw et al.28 demonstrated that the elevation of serum AFP levels (>20 ng/ml) could be found in 45.6% of chronic hepatitis B patients during follow-up in the absence of HCC. Consequently, the higher cut-off level of AFP for evaluating AFP response avoids disturbances as a result of hepatitis flare-up and exhibits significant changes in AFP levels after RFA therapy. Thus, the impact of AFP response on post-RFA prognosis was not applied to the patients with baseline serum AFP levels less than 100 ng/ml in the present study. Similarly, Tsai and colleagues also only enrolled HCC patients who had baseline serum AFP levels of >100 ng/ml for predicting post-RFA prognosis stratified by adequate AFP decrease in their cohort.22 A recent study by Shao et al.,20 arbitrarily used a 20% decrease in serum AFP from baseline within the first 4 weeks of treatment as a response criterion in their analyses. They showed that AFP responders had significantly longer progression-free survival and overall survival than nonresponders in patients with advanced HCC who received anti-angiogenic therapy. The present study adopted a 20% reduction from baseline to determine AFP response in patients with higher baseline AFP levels (>100 ng/ml).
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Table 2 Comparison of demographic data between patients with an optimal and non-optimal alpha-fetoprotein (AFP) response after radiofrequency ablation (RFA). Total (n ¼ 58)
Parameter
Patient demographics Age (years) (mean SD) 68.2 10.8 Sex (M:F) (%) 34/24 (58.6%/41.4%) Serum biochemistry tests and liver function testsa Albumin (g/dl) 3.8; 3.4e4.1 Total bilirubin (mg/dl) 0.8; 0.6e1.2 ALT (U/L) 43; 29e88 Creatinine (mg/dl) 0.9; 0.8e1.1 Alk-P (U/L) 106.5; 80.8e130.3 ICG-15R (%) 15; 13e29 PT-INR 1.1; 1e1.1 126,500; 85,500e221,000 Platelet (/mm3) ChildePugh A/B 51/7 (87.9%/12.1%) Viral factors HBsAg (positive/negative) 26/29 (44.8%/50%) Anti-HCV 27/27 (46.6%/46.6%) (positive/negative) Antiviral agents 10/48 (17.2%/82.8%) (yes/no) Tumour factorsa Tumour size (cm) 2.5; 1.9e3 Single/multi-nodularity (%) 50/8 (86.2%/13.8%) AFP (ng/ml) 303.5; 161e1002.8
Optimal (n ¼ 46)
Non-optimal (n ¼ 12)
P
66.8 10.9 28/18 (60.9%/39.1%)
73.8 8.9 6/6 (50%/50%)
0.047 0.527
3.9; 3.4e4.2 0.8; 0.6e1.2 43; 28.8e94 0.9; 0.8e1.1 108; 79.3e127.3 17; 13.5e33 1.1; 1e1.1 116,500; 87,000e160,250 42/4 (91.3%/8.7%)
3.6; 3e3.8 1; 0.5e1.7 42.5; 29.3e65.3 1; 0.8e1.7 100.5; 82e141.3 13; 12e14 1; 1e1.1 106,500; 81,500e189,250 9/3 (75%/25%)
0.161 0.276 0.065 0.315 0.941 0.362 0.771 0.692 0.147
22/21 (47.8%/45.7%) 18/25 (39.1%/54.3%)
4/8 (33.3%/66.7%) 9/2 (75%/16.7%)
0.443 0.043
9/37 (19.6%/80.4%)
1/11 (8.3%/91.7%)
0.670
2.5; 1.8e2.8 41/5 (89.1%/10.9%) 257; 144e528.5
3.1; 2.6e4 9/3 (75%/25%) 1515;368.5e5610.5
0.011 0.342 0.046
M/F, male/female; ALT, alanine aminotransferase; Alk-P, alkaline phosphatase; ICG-15R, indocyanine green dye retention rate at 15 minutes; PT-INR, prothrombin time international normalized ratio; HBsAg, hepatitis B serum antigen; HCV, hepatitis C virus; AFP, alpha-fetoprotein. a Continuous variables are expressed as median; 25 and 75 percentiles.
The results are comparable to previous studies conducted for systemic anti-angiogenic therapy, suggesting the applicability of AFP response for HCC patients after RFA. Change in tumour size and the amount of enhancing tissue in the treated area by contrast-enhanced imaging are recommended for evaluating treatment response for HCC patients undergoing non-surgical therapies.23,29 However, evaluating the size of contrast-enhanced area is subjective. Moreover, in the registration study of sorafenib for treating patients with advanced HCC, although tumour shrinkage was achieved in only 3% of patients, the overall survival significantly improved in patients treated with sorafenib.30 One recent study further demonstrated that a total of 16% of patients who achieved complete response after
Table 3 Factors of poor overall survival and recurrence for patients with a baseline serum alpha-fetoprotein (AFP) of 100 ng/ml and successful radiofrequency ablation (RFA) treatment by multivariate analysis. Variable Survival PT INR >1.1/1.1 Non-optimal/optimal AFP response Creatinine >1.5/1.5 mg/dl Recurrence Platelet 105/>105/mm3 Non-optimal/optimal AFP response Tumour size >2 cm/2 cm
Case Hazard 95% Confidence p-Value number ratio intervals 18/40 12/46
8.243 5.481
1.677e40.518 1.271e23.632
0.009 0.023
5/53
11.195 1.446e86.672
0.021
25/33 12/46
1.936 4.220
1.006e3.728 1.941e9.176
0.048 <0.001
38/20
2.360
1.100e5.062
0.027
PT-INR, prothrombin time international normalized ratio.
loco-regional therapies as per the EASL guidelines, which showed no enhancing tissue at CT, still had viable tumour in the subsequent pathological examination at liver transplantation or resection surgery.31 Thus, treatment response assessed by imaging studies is not perfect in patients treated by loco-regional therapy and chemotherapy. As AFP can be measured simply, rapidly, reliably, and objectively, the AFP response can be an ancillary tool for evaluating treatment response and predicting post-therapy prognosis for HCC patients undergoing RFA. In the present cohort, the impact of serum AFP levels on the prognosis of HCC patients after RFA therapy was demonstrated in two ways. First, patients with high baseline serum AFP levels had a significantly poorer overall survival and higher incidence of developing recurrence. Yamamoto et al.32 shows that higher serum AFP levels are associated with higher rates of vascular invasion, capsular infiltration, and poor tumour differentiation for HCC patients undergoing hepatectomy. The study suggests that serum AFP levels may also reflect tumour biology, thereby determining the prognosis of HCC patients after therapies. Second, in patients with baseline serum AFP levels of 100 ng/ml, a non-optimal AFP response is an independent poor prognostic factor, both in terms of survival and recurrence. This implies that monitoring serial serum AFP levels before and after therapy is mandatory for HCC patients undergoing RFA. In the present study, HCC patients with a non-optimal AFP response after RFA are older and have higher rates of chronic HCV infection, larger tumour sizes, and higher baseline AFP levels than those with an optimal AFP response. These patients may need closer monitoring for tumour recurrence after RFA therapy.
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The confirmation of RFA response in this study is determined by complete tumour necrosis 1 month after RFA therapy as demonstrated at CT or MRI.4 All patients with a non-optimal AFP response had tumour recurrence within 2 years after RFA, even though they initially achieved complete tumour necrosis after therapy, as shown by imaging studies. Consequently, clinicians should be more aware of the emergence of recurrence in patients with high baseline AFP values and a non-optimal AFP response after RFA therapy, which implies that residual, non-detectable tumours may be present. There may be two strategies for treating such patients: one is by closer monitoring using serial serum AFP levels and imaging, and the other is prescribing anti-tumour target therapy such as sorafenib. More large-scale, prospective studies are warranted to confirm this hypothesis. In the present cohort, most patients achieved complete tumour necrosis after one to two sessions of RFA therapy and only 14 patients (4.5%) had treatment failure. The latter patients had significantly larger tumour sizes than those with successful treatment (median tumour size 3.1 versus 2.2 cm). This result is consistent with previous studies.9,10,33e35 Baldan et al.33 demonstrated that the possibility of obtaining complete tumour ablation substantially decreases when the tumour size exceeds 3 cm. As such, for HCC patients with larger tumour sizes, a combination of treatment modalities may be warranted to improve the efficacy of RFA. In several retrospective studies and preliminary data of randomized, controlled trials, combining TACE with RFA has been shown to be more effective than RFA alone in terms of extending the ablated area and decreasing local tumour progression.34,36e38 However, the long-term outcomes between combination therapy and RFA alone for treating HCC of larger tumour size still needs to be elucidated with more prospective studies. The retrospective data analysis and small case numbers are the major limitations of the present study. Second, only a small proportion of patients with small HCC undergoing RFA had elevated serum AFP levels. More large-scale, prospective studies are warranted to confirm the application of AFP response in predicting prognosis after RFA. Third, beside AFP response, previous studies demonstrate that tumour biology and morphology also play important roles in determining the outcomes of HCC. Patients with well-defined encapsulated tumours have a higher rate of local tumour control after RFA or TACE and better prognosis than those with diffuse poorly marginated tumors.39e41 As this is a retrospective study, there were no detailed imaging characteristics or tumour biology before RFA; therefore, the efficacy of treatment and prognosis of patients by tumour morphology and biology could not be compared. In conclusion, the present study demonstrates that serum AFP response may be a useful marker for predicting prognosis in HCC patients undergoing RFA.
Acknowledgements This study was supported by grants from the National Science Council, Taiwan (97-2314-B-075-035, 98-2314-B-
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075-030-MY2), Taipei Veterans General Hospital (V97A033, V98A-072, V98C1-120, V100A-034, V100C-034), and the Center of Excellence for Cancer Research at TVGH (DOH100-TD-C-111-007), Taipei, Taiwan. Writing assistance was provided by Gene Alzona Nisperos, MD.
Supplementary material Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.crad.2011.10. 009.
References 1. Omata M, Lesmana LA, Tateishi R, et al. Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma. Hepatol Int 2010;4:439e74. 2. Hung HH, Su CW, Lai CR, et al. Fibrosis and AST to platelet ratio index predict post-operative prognosis for solitary small hepatitis B-related hepatocellular carcinoma. Hepatol Int 2010;4:691e9. 3. Lee SM, Won JY, Lee DY, et al. Percutaneous cryoablation of small hepatocellular carcinomas using a 17-gauge ultrathin probe. Clin Radiol 2011;66:752e9. 4. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005;42:1208e36. 5. Huang J, Yan L, Cheng Z, et al. A randomized trial comparing radiofrequency ablation and surgical resection for HCC conforming to the Milan criteria. Ann Surg 2010;252:903e12. 6. Lencioni R. Loco-regional treatment of hepatocellular carcinoma. Hepatology 2010;52:762e73. 7. Germani G, Pleguezuelo M, Gurusamy K, et al. Clinical outcomes of radiofrequency ablation, percutaneous alcohol and acetic acid injection for hepatocelullar carcinoma: a meta-analysis. J Hepatol 2010;52:380e8. 8. Lin SM, Lin CJ, Lin CC, et al. Randomised controlled trial comparing percutaneous radiofrequency thermal ablation, percutaneous ethanol injection, and percutaneous acetic acid injection to treat hepatocellular carcinoma of 3 cm or less. Gut 2005;54:1151e6. 9. Brunello F, Veltri A, Carucci P, et al. Radiofrequency ablation versus ethanol injection for early hepatocellular carcinoma: a randomized controlled trial. Scand J Gastroenterol 2008;43:727e35. 10. N’Kontchou G, Mahamoudi A, Aout M, et al. Radiofrequency ablation of hepatocellular carcinoma: long-term results and prognostic factors in 235 Western patients with cirrhosis. Hepatology 2009;50:1475e83. 11. Tateishi R, Shiina S, Teratani T, et al. Percutaneous radiofrequency ablation for hepatocellular carcinoma. An analysis of 1000 cases. Cancer 2005;103:1201e9. 12. Hung HH, Chiou YY, Hsia CY, et al. Survival rates are comparable after radiofrequency ablation or surgery in patients with small hepatocellular carcinomas. Clin Gastroenterol Hepatol 2011;9:79e86. 13. Kim H, Rhim H, Choi D, et al. Recurrence and treatment pattern in long-term survivors with hepatocellular carcinoma: a comparison between radiofrequency ablation and surgery as a first-line treatment. World J Surg 2010;34:1881e6. 14. Kao WY, Chiou YY, Hung HH, et al. Risk factors for long-term prognosis in hepatocellular carcinoma after radiofrequency ablation therapy: the clinical implication of aspartate aminotransferase-platelet ratio index. Eur J Gastroenterol Hepatol 2011;23:528e36. 15. Livraghi T, Meloni F, Di Stasi M, et al. Sustained complete response and complications rates after radiofrequency ablation of very early hepatocellular carcinoma in cirrhosis: is resection still the treatment of choice? Hepatology 2008;47:82e9. 16. Choi D, Lim HK, Rhim H, et al. Percutaneous radiofrequency ablation for early-stage hepatocellular carcinoma as a first-line treatment: longterm results and prognostic factors in a large single-institution series. Eur Radiol 2007;17:684e92.
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17. Wu JC, Huang YH, Chau GY, et al. Risk factors for early and late recurrence in hepatitis B-related hepatocellular carcinoma. J Hepatol 2009; 51:890e7. 18. Chen LT, Liu TW, Chao Y, et al. Alpha-fetoprotein response predicts survival benefits of thalidomide in advanced hepatocellular carcinoma. Aliment Pharmacol Ther 2005;22:217e26. 19. Chan SL, Mo FK, Johnson PJ, et al. New utility of an old marker: serial alpha-fetoprotein measurement in predicting radiologic response and survival of patients with hepatocellular carcinoma undergoing systemic chemotherapy. J Clin Oncol 2009;27:446e52. 20. Shao YY, Lin ZZ, Hsu C, et al. Early alpha-fetoprotein response predicts treatment efficacy of antiangiogenic systemic therapy in patients with advanced hepatocellular carcinoma. Cancer 2010;116:4590e6. 21. Riaz A, Ryu RK, Kulik LM, et al. Alpha-fetoprotein response after locoregional therapy for hepatocellular carcinoma: oncologic marker of radiologic response, progression, and survival. J Clin Oncol 2009;27: 5734e42. 22. Tsai MC, Wang JH, Hung CH, et al. Favorable alpha-fetoprotein decrease as a prognostic surrogate in patients with hepatocellular carcinoma after radiofrequency ablation. J Gastroenterol Hepatol 2010;25:605e12. 23. Bruix J, Sherman M, Llovet JM, et al. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol 2001;35:421e30. 24. Vora SR, Zheng H, Stadler ZK, et al. Serum alpha-fetoprotein response as a surrogate for clinical outcome in patients receiving systemic therapy for advanced hepatocellular carcinoma. Oncologist 2009;14:717e25. 25. Shirabe K, Takenaka K, Gion T, et al. Significance of alpha-fetoprotein levels for detection of early recurrence of hepatocellular carcinoma after hepatic resection. J Surg Oncol 1997;64:143e6. 26. Sherman M. The resurrection of alphafetoprotein. J Hepatol 2010;52: 939e40. 27. Tateishi R, Shiina S, Yoshida H, et al. Prediction of recurrence of hepatocellular carcinoma after curative ablation using three tumor markers. Hepatology 2006;44:1518e27. 28. Liaw YF, Tai DI, Chen TJ, et al. Alpha-fetoprotein changes in the course of chronic hepatitis: relation to bridging hepatic necrosis and hepatocellular carcinoma. Liver 1986;6:133e7. 29. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92:205e16.
30. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378e90. 31. Riaz A, Memon K, Miller FH, et al. Role of the EASL, RECIST, and WHO response guidelines alone or in combination for hepatocellular carcinoma: radiologicepathologic correlation. J Hepatol 2011;54:695e704. 32. Yamamoto K, Imamura H, Matsuyama Y, et al. Significance of alpha-fetoprotein and des-gamma-carboxy prothrombin in patients with hepatocellular carcinoma undergoing hepatectomy. Ann Surg Oncol 2009;16:2795e804. 33. Baldan A, Marino D, Deg M, et al. Percutaneous radiofrequency thermal ablation for hepatocellular carcinoma. Aliment Pharmacol Ther 2006;24:1495e501. 34. Morimoto M, Numata K, Kondou M, et al. Midterm outcomes in patients with intermediate-sized hepatocellular carcinoma: a randomized controlled trial for determining the efficacy of radiofrequency ablation combined with transcatheter arterial chemoembolization. Cancer 2011;116:5452e60. 35. Lam VW, Ng KK, Chok KS, et al. Incomplete ablation after radiofrequency ablation of hepatocellular carcinoma: analysis of risk factors and prognostic factors. Ann Surg Oncol 2008;15:782e90. 36. Kirikoshi H, Saito S, Yoneda M, et al. Outcome of transarterial chemoembolization monotherapy, and in combination with percutaneous ethanol injection, or radiofrequency ablation therapy for hepatocellular carcinoma. Hepatol Res 2009;39:553e62. 37. Fuke H, Sugimoto K, Shiraki K, et al. Predictive factors for distant recurrence of HCV-related hepatocellular carcinoma after radiofrequency ablation combined with chemoembolization. Aliment Pharmacol Ther 2008;27:1253e60. 38. Veltri A, Moretto P, Doriguzzi A, et al. Radiofrequency thermal ablation (RFA) after transarterial chemoembolization (TACE) as a combined therapy for unresectable non-early hepatocellular carcinoma (HCC). Eur Radiol 2006;16:661e9. 39. Lopez Jr RR, Pan SH, Hoffman AL, et al. Comparison of transarterial chemoembolization in patients with unresectable, diffuse vs focal hepatocellular carcinoma. Arch Surg 2002;137:653e7. 40. Seror O, N’Kontchou G, Ibraheem M, et al. Large (>or¼5.0-cm) HCCs: multipolar RF ablation with three internally cooled bipolar electrodesdinitial experience in 26 patients. Radiology 2008;248:288e96. 41. Barakat O, Wood RP, Ozaki CF, et al. Morphological features of advanced hepatocellular carcinoma as a predictor of downstaging and liver transplantation: an intention-to-treat analysis. Liver Transpl 2010;16: 289e99.
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Serum alpha-fetoprotein response can predict prognosis in hepatocellular carcinoma patients undergoing radiofrequency ablation therapy W.-Y. Kao a, Y.-Y. Chiou b, c, *, H.-H. Hung a, c, C.-W. Su a, c, d, **, Y.-H. Chou b, c, J.-C. Wu d, e, T.-I. Huo a, f, Y.-H. Huang a, d, W.-C. Wu a, H.-C. Lin a, c, S.-D. Lee a, c a
Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taiwan Department of Radiology, Taipei Veterans General Hospital, Taiwan c Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan d Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan e Department of Medical Research and Education, Taipei Veterans General Hospital, Taiwan f Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan b
art icl e i nformat ion Article history: Received 28 June 2011 Received in revised form 11 September 2011 Accepted 25 October 2011
AIMS: To evaluate the clinical inference of serum alpha-fetoprotein (AFP) response in hepatocellular carcinoma (HCC) patients undergoing percutaneous radiofrequency ablation (RFA). MATERIALS AND METHODS: Three hundred and thirteen previously untreated HCC patients were enrolled in the study. The optimal AFP response was defined as >20% decrease from baseline after 1 month of RFA for those with a baseline AFP level of 100 ng/ml. The impact of AFP response on prognosis was analysed and prognostic factors were assessed. RESULTS: After a median follow-up of 26.7 19.1 months, 49 patients died and 264 patients were alive. The cumulative 5 year survival rates were 75.3 and 57.4% in patients with an initial AFP of <100 ng/ml and 100 ng/ml, respectively (p ¼ 0.003). In the 58 patients with a baseline AFP of 100 ng/ml and initial completed tumour necrosis after RFA, the cumulative 5 year survival rates were 62.4 and 25.7% in optimal and non-optimal AFP responders, respectively (p ¼ 0.001). By multivariate analysis, the prothrombin time international normalized ratio >1.1 (p ¼ 0.009), nonoptimal AFP response (p ¼ 0.023), and creatinine >1.5 mg/dl (p ¼ 0.021) were independent risk factors predictive of poor overall survival. Besides, the cumulative 5 year recurrence rates were 83.4 and 100% in optimal and non-optimal AFP responders, respectively (p < 0.001). Multivariate analysis demonstrated platelet count 105/mm3 (p ¼ 0.048), tumour size >2 cm (p ¼ 0.027), and non-optimal AFP response (p < 0.001) were independent risk factors associated with tumour recurrence after RFA. CONCLUSIONS: Serum AFP response may be a useful marker for predicting prognosis in HCC patients undergoing RFA. Ó 2011 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
* Guarantor and correspondent: Y.-Y. Chiou, Division of Gastrointestinal Radiology, Department of Radiology, Taipei Veterans General Hospital, 201 Shih-Pai Road, Sec. 2, Taipei 112, Taiwan. Tel.: þ886 2 28712121x7594; fax: þ886 2 28769310. ** Guarantor and correspondent: C.-W. Su, Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, 201 Shih-Pai Road, Sec.2, Taipei 112, Taiwan. Tel.: +886 2 28712121x3971; fax: + 886 2 28739318. E-mail addresses: [email protected] (Y.-Y. Chiou), cwsu2@vghtpe. gov.tw (C.-W. Su).
Introduction Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths in the world.1e3 Surgical resection, liver transplantation, and local ablation therapies are currently recognized as potentially curative treatment modalities.4 Although resection surgery and liver
0009-9260/$ e see front matter Ó 2011 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.crad.2011.10.009
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transplantation can provide better overall survival and lower rates of recurrence after therapy, they are often unfeasible due to the shortage of liver transplantation donors or the relatively poor liver functional reserve of the patients, which makes resection surgery impossible.5 Consequently, local ablation therapies have been introduced for the management of small HCC in patients that are not eligible for liver transplantation or resection therapy. Among local ablation therapies, percutaneous radiofrequency ablation (RFA) is superior to other therapies due to fewer therapy sessions, better local tumour control, and higher survival rates.6e9 Accordingly, RFA has been widely applied in patients with small HCC in recent years.10e14 Nevertheless, patients undergoing RFA have a high incidence of recurrence after completing ablation of the primary tumour. It is estimated that the cumulative 5 year recurrence rate of patients undergoing RFA is more than 70%.11,12,14e16 To improve the long-term outcome of RFA, it is crucial to elucidate the mechanisms and risks factors associated with recurrence after RFA. The serum alpha-fetoprotein (AFP) level has been widely applied as a screening, diagnostic, and prognostic tool in HCC.16,17 However, its role in monitoring treatment response and long-term prognosis has not been fully elucidated. Recently, dynamic changes of serum AFP levels reportedly reflect responses to chemotherapy18e20 and trans-arterial chemoembolization (TACE) in intermediate or advanced HCC.21 Nevertheless, studies evaluating the impact of AFP response on the prognosis of patients with small HCC after RFA are still few.22 The aim of the present study was to evaluate the clinical implications of AFP response in HCC patients undergoing RFA.
Patients and methods Patients and follow-up The present study complied with the standards of the Declaration of Helsinki and was approved by the Institutional Review Board (IRB). This cohort study retrospectively reviewed HCC patients who were not suitable or refused to resection surgery or liver transplantation and underwent RFA in Taipei Veterans General Hospital from 1 January 2002 to 31 December 2009. The choice of RFA was decided by the patients after the physicians explained the advantage, side effects, and prognosis among the various therapy modalities, including resection surgery, liver transplantation, local ablation therapy, TACE, and chemotherapy. After review of medical chart records, 313 consecutive HCC patients who fulfilled the diagnostic criteria of HCC by the American Association for the Study of Liver Disease (AASLD consensus, 2005)4 and underwent RFA as the first treatment modality were enrolled. The inclusion criteria were tumour size <5 cm without extra-hepatic metastasis; three or fewer tumours; grade A or B ChildePugh classification of liver function; and no other major diseases that
might complicate RFA. The RFA procedure was as previously described.12 Dynamic computed tomography (CT) was undertaken 1 month after all of the tumours were ablated by RFA. Magnetic resonance imaging (MRI) was performed in patients with allergies to the CT contrast medium, renal insufficiency, or inconclusive CT diagnosis. For confirmed residual tumours, a second session of RFA was conducted. If viable tumours persisted after two RFA sessions, treatment was considered a failure. When all of the tumours had been successfully destroyed and without any residual viable tumours confirmed by CT or MRI, the patient was followed-up with testing for serum liver function tests, AFP levels, and ultrasonography every 3 months; and CT or MRI every 6 months until 30 September 2010. The start date of follow-up for tumour recurrence was the day that all of the tumours ablated by RFA were confirmed by CT or MRI. Tumour recurrence was suspected if there was an elevated serum AFP level (>20 ng/ml) or new lesion detected by surveillance ultrasonography. These were confirmed and diagnosed by dynamic CT or MRI. When recurrent tumours were diagnosed, patients were treated with the appropriate management, including repeated RFA, percutaneous ethanol injection therapy, TACE, resection surgery, liver transplantation, chemotherapy, radiotherapy, or supportive treatment.
Biochemical and serological markers Serum hepatitis B surface antigens (HBsAg) were tested using radio-immunoassay (Abbott Laboratories, North Chicago, IL, USA), and antibodies to hepatitis C virus (HCV) were measured using a second-generation enzyme immunoassay (Abbott Laboratories, North Chicago, IL). Serum liver function tests, including albumin, bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (Alk-P), gamma-glutamyltransferase (GGT), blood urea nitrogen (BUN), creatinine, and glucose levels, were measured using a systemic multi-auto-analyser (Technicon SMAC, Technicon Instruments, Tarrytown, NY, USA). Serum AFP level was measured by radio-immunoassay (Serono Diagnostic SA, Coinsin/VD, Switzerland). An optimal AFP response was defined as >20% decrease from baseline after 1 month of RFA.19,20
Statistical analysis The baseline characteristics to be evaluated with outcomes were selected by the European Association for the Study of the Liver (EASL) guidelines published in 2001.23 Pearson’s chi-square analysis or Fisher’s exact test were used to compare categorical variables. As this cohort was composed of non-normal distribution populations, the nonparametric test of the ManneWhitney U-test was used to compare continuous variables of demographic data between patients with baseline serum AFP <100 ng/ml and AFP 100 ng/ml, with successful and failed RFA treatment, and with optimal and non-optimal AFP responses after RFA,
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respectively. Cumulative recurrence rates or overall survival rates were estimated by the KaplaneMeier method and compared using the Cox’s proportional hazards model. Variables with statistical significance (p < 0.05) or proximate to it (p < 0.1) by univariate analysis underwent multivariate analysis via forward stepwise Cox’s regression model. A two-tailed p < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS 17.0 for Windows (SPSS, Chicago, IL, USA).
Results Demographics data of RFA patients The demographic characteristics of all patients are shown in Table 1. Of the 313 patients, 262 were successfully treated with one RFA session and 37 had two sessions (Fig 1), for a treatment success rate of 95.5%. The remaining 14 patients with treatment failure underwent further RFA or TACE as rescue therapies. Patients with RFA treatment failure had a significantly larger tumour size (p < 0.001) than those with complete tumour necrosis after one to two sessions of RFA therapy. Besides, 158 patients had normal baseline serum AFP levels (<20 ng/ml), 93 patients had AFP levels between 20 and 100 ng/ml, and the remaining 62 patients had an AFP level of l00 ng/ml. Demographic data between patients with initial serum AFP levels of 100 ng/ ml and those with <100 ng/ml are shown in Supplementary Material Table S1. There was a trend for patients with an initial serum AFP levels of <100 ng/ml to have a smaller
431
tumour size (p ¼ 0.066). Liver functional reserve, age, sex, and viral factors were comparable between the two groups. In the study cohort, 59 patients received anti-viral therapy after RFA, including 18 patients with lamivudine, 15 patients with entecavir, and 26 patients with pegylated interferon therapy.
Factors associated with overall survival and recurrence After median follow-up of 26.7 19.1 months, 49 patients died and 264 were still alive. The overall cumulative survival rates at 1, 2, 3, and 5 years were 96.6, 88.5, 81, and 72.3%, respectively. Stratified by the baseline serum AFP level, the overall cumulative survival rates at 1, 2, 3, and 5 years were 97.5%, 90.9, 84.3, and 75.3%, respectively, in patients with an initial AFP of <100 ng/ml, and 92.5, 75.6, 63.1, and 57.4%, respectively, in patients with a serum AFP of 100 ng/ml (p ¼ 0.003, Fig 2a). In the 299 patients with complete tumour necrosis after one to two sessions of RFA therapy confirmed by CT or MRI, 190 had tumour recurrence, with 12.3 16.4 months median time of development. The cumulative rate of recurrence at 1, 2, 3, and 5 years were 40.1, 57.7, 72.3, and 80.6%, respectively. Stratified by baseline AFP levels, the cumulative recurrence rates at 1, 2, 3, and 5 years were 37.9, 53.6, 68.9, and 78.5%, respectively, in patients with a serum AFP of <100 ng/ml and 53.6, 74.8, 87.1, and 87.1%, respectively, in patients with an AFP of 100 ng/ml (p ¼ 0.002, Fig 2b).
Table 1 Comparison of demographic data between patients with successful and failed radiofrequency ablation (RFA) treatment. Parameter
Total (n ¼ 313)
Patient demographics Age (years) (mean SD) 68.1 11.3 Sex (M/F) (%) 199/114 (63.6%/36.4%) Serum biochemistry tests and liver function testsa Albumin (g/dl) 3.9; 3.4e4.2 Total bilirubin (mg/dl) 0.8; 0.5e1.2 ALT (U/L) 51; 35.0e90.5 Creatinine (mg/dl) 1; 0.8e1.2 Alk-P(U/L) 95; 71.3e126 ICG-15R (%) 17; 9.8e29 PT-INR 1; 1e1.1 113,000; 83,500e157,000 Platelet (/mm3) ChildePugh A/B 274/38 (87.5%/12.1%) Viral factors HBsAg 134/160 (positive/negative) (44.7%/53.3%) Anti-HCV 142/155 (positive/negative) (47.2%/51.5%) Antiviral agents 59/254 (yes/no) (18.8%/81.2%) Tumour factors Tumour size (cm) 2.3; 1.6e2.9 Single/multi-nodularity (%) 263/50 (84%/16%) AFP (ng/mL) 19.6; 8e60.8 AFP 100 ng/ml (%) 251/62 (80.2%/19.8%)
Success (n ¼ 299)
Failure (n ¼ 14)
67.9 11.4 190/109 (63.5%/36.5%)
72.1 8.9 9/5 (66.7%/33.3%)
0.168 1.000
3.9; 3.4e4.2 0.8; 0.5e1.2 51.0; 32.0e92 1; 0.8e1.2 95; 76e128 17.5; 9e29 1; 1e1.1 113,000; 82,000e156,000 261/37 (87.3%/12.4%)
4.2; 3.6-4.4 0.9; 0.6e1.0 38.5; 31.5e63 1; 0.7e1.2 80; 64.5e112.5 16; 11e35.5 1; 1e1.1 110,000; 87,250e169,500 13/1 (92.7%/7.1%)
0.150 0.533 0.358 0.732 0.950 0.998 0.226 0.700 0.530
126/154 (44.1%/53.8%) 137/146 (47.7%/50.9%) 57/242 (19.1%/80.9%)
8/6 (57.1%/42.9%) 5/9 (35.7%/64.3%) 2/12 (14.3%/85.7%)
0.538
2.2; 1.6e2.9 251/48 (83.9%/16.1%) 19.9; 8e60 241/58 (80.6%/19.4%)
3.1; 2.8e3.9 12/2 (85.7%/14.3%) 10.9; 4.9e173.5 10/4 (71.4%/28.6%)
p
0.513 1.000
<0.001 1.000 0.810 0.489
M/F, male/female; ALT, alanine aminotransferase; Alk-P, alkaline phosphatase; ICG-15R, indocyanine green dye retention rate at 15 minutes; PT-INR, prothrombin time international normalized ratio; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; AFP, alpha-fetoprotein. a Continuous variables are expressed as median; 25 and 75 percentiles.
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Figure 1 Flow chart summarizing the treatment courses of the enrolled patients.
Factors associated with overall survival in patients with baseline serum AFP 100 ng/ml and successful treatment Fifty-eight patients with baseline serum AFP levels 100 ng/ml had complete tumour necrosis after one to two sessions of RFA therapy (Fig 1). There was an optimal AFP response in 46 patients, with >20% reduction in serum AFP levels from baseline after 1 month of RFA therapy. The remaining 12 patients were defined as AFP non-optimal responders. Demographic characteristics between patients with and without an optimal AFP response are compared in Table 2. Patients in the non-optimal AFP response group were older (p ¼ 0.047) and there was a higher incidence of chronic carriers of hepatitis C virus (HCV; p ¼ 0.043). Conversely, patients in the optimal AFP response group had smaller tumour sizes (p ¼ 0.011) and lower baseline serum AFP levels (p ¼ 0.046). The cumulative overall survival rates at 1, 2, 3, and 5 years were 97.5, 86.3, 70.2, and 62.4%, respectively, in patients with an optimal AFP response, and 68.5, 25.7, 25.7, and 25.7%, respectively, in AFP non-optimal responders. Overall survival rates were significantly higher in HCC patients with an optimal AFP response (p ¼ 0.001, Fig 2c). Univariate analysis indicated that the following were associated with poor overall survival: lower serum albumin levels (3.7 g/dl), lower platelet counts (<105/mm3), higher prothrombin time (PT) international normalized ratio (INR; > 1.1), non-optimal AFP response, larger tumour size (>2 cm),
and higher serum creatinine levels (>1.5 mg/dl; Supplementary Material Table S2). Older patients (age >65 years) had a trend of poor overall survival (p ¼ 0.094). By multivariate analysis, PT INR >1.1 [hazard ratio (HR) 8.243, p ¼ 0.009], non-optimal AFP response (HR 5.481, p ¼ 0.023), and creatinine >1.5 mg/dl (HR 11.195, p ¼ 0.021) were independent risk factors predictive of poor overall survival in patients with initial serum AFP levels of 100 ng/ ml and complete tumour necrosis after one to two sessions of RFA therapy (Table 3).
Factors associated with recurrence after RFA in patients with baseline serum AFP 100 ng/ml and successful treatment In this sub-cohort, the cumulative recurrence rates at 1, 2, 3, and 5 years were 43.5, 67.7, 83.4, and 83.4%, respectively, in patients with optimal AFP response and 91.7, 100, 100, and 100%, respectively, in AFP non-optimal responders. The total recurrence rates were significantly higher in patients with a non-optimal AFP response (p < 0.001, Fig 2d), all of whom developed recurrence within 2 years after RFA therapy. Multivariate analysis showed that a platelet count of 105/mm3 (HR 1.936, p¼0.048), a non-optimal AFP response (HR 4.220, p < 0.001), and tumour size >2 cm (HR 2.360, p ¼ 0.027) were independent risk factors associated with higher incidence of recurrence after RFA in patients with initial serum AFP levels 100 ng/ml and complete tumour necrosis after one to two sessions of RFA therapy (Table 3).
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433
Figure 2 Cumulative overall survival and recurrence rates stratified by initial serum AFP levels and AFP response. Patients with initial serum AFP levels of 100 ng/ml had (a) lower overall survival rates (p ¼ 0.003) and (b) a higher incidence of recurrence (p ¼ 0.002) than those with an initial serum AFP of <100 ng/ml. For patients with initial serum AFP levels of 100 ng/ml, those with an optimal AFP response after RFA had (c) better overall survival rates (p ¼ 0.001) and (d) lower incidences of recurrence (p < 0.001) than those with a non-optimal AFP response.
Discussion Although AFP measurements have been undertaken for the diagnosis of HCC in recent decades, serial AFP levels have not been widely applied for monitoring treatment response after RFA therapy. The results of the present study shows that patients with an adequate AFP response, defined by a decline of more than 20% 1 month after RFA therapy, have a better prognosis than those with a non-optimal response. This result is consistent with other observational studies of HCC patients receiving surgery, locoregional therapies, and systemic chemotherapy.19e22,24,25 The decline in AFP levels after therapy is likely a reflection of decreased tumour burden.26 In contrast, elevation of serum AFP levels after anti-tumour therapy also likely represents re-expansion of the tumour, either by incomplete treatment or the development of de novo new growth. Consequently, an optimal AFP response may serve as an easy, objective, and non-invasive tool to monitor the emergence of recurrence after RFA. It is recommended that serial AFP levels be checked before and 1 month after RFA for HCC patients with elevated AFP levels. According to the study conducted by Tateishi et al.,27 when baseline serum AFP levels are <100 ng/ml, most
patients show no significant change in AFP levels after RFA therapy. The present cohort also had similar findings. Moreover, Liaw et al.28 demonstrated that the elevation of serum AFP levels (>20 ng/ml) could be found in 45.6% of chronic hepatitis B patients during follow-up in the absence of HCC. Consequently, the higher cut-off level of AFP for evaluating AFP response avoids disturbances as a result of hepatitis flare-up and exhibits significant changes in AFP levels after RFA therapy. Thus, the impact of AFP response on post-RFA prognosis was not applied to the patients with baseline serum AFP levels less than 100 ng/ml in the present study. Similarly, Tsai and colleagues also only enrolled HCC patients who had baseline serum AFP levels of >100 ng/ml for predicting post-RFA prognosis stratified by adequate AFP decrease in their cohort.22 A recent study by Shao et al.,20 arbitrarily used a 20% decrease in serum AFP from baseline within the first 4 weeks of treatment as a response criterion in their analyses. They showed that AFP responders had significantly longer progression-free survival and overall survival than nonresponders in patients with advanced HCC who received anti-angiogenic therapy. The present study adopted a 20% reduction from baseline to determine AFP response in patients with higher baseline AFP levels (>100 ng/ml).
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Table 2 Comparison of demographic data between patients with an optimal and non-optimal alpha-fetoprotein (AFP) response after radiofrequency ablation (RFA). Total (n ¼ 58)
Parameter
Patient demographics Age (years) (mean SD) 68.2 10.8 Sex (M:F) (%) 34/24 (58.6%/41.4%) Serum biochemistry tests and liver function testsa Albumin (g/dl) 3.8; 3.4e4.1 Total bilirubin (mg/dl) 0.8; 0.6e1.2 ALT (U/L) 43; 29e88 Creatinine (mg/dl) 0.9; 0.8e1.1 Alk-P (U/L) 106.5; 80.8e130.3 ICG-15R (%) 15; 13e29 PT-INR 1.1; 1e1.1 126,500; 85,500e221,000 Platelet (/mm3) ChildePugh A/B 51/7 (87.9%/12.1%) Viral factors HBsAg (positive/negative) 26/29 (44.8%/50%) Anti-HCV 27/27 (46.6%/46.6%) (positive/negative) Antiviral agents 10/48 (17.2%/82.8%) (yes/no) Tumour factorsa Tumour size (cm) 2.5; 1.9e3 Single/multi-nodularity (%) 50/8 (86.2%/13.8%) AFP (ng/ml) 303.5; 161e1002.8
Optimal (n ¼ 46)
Non-optimal (n ¼ 12)
P
66.8 10.9 28/18 (60.9%/39.1%)
73.8 8.9 6/6 (50%/50%)
0.047 0.527
3.9; 3.4e4.2 0.8; 0.6e1.2 43; 28.8e94 0.9; 0.8e1.1 108; 79.3e127.3 17; 13.5e33 1.1; 1e1.1 116,500; 87,000e160,250 42/4 (91.3%/8.7%)
3.6; 3e3.8 1; 0.5e1.7 42.5; 29.3e65.3 1; 0.8e1.7 100.5; 82e141.3 13; 12e14 1; 1e1.1 106,500; 81,500e189,250 9/3 (75%/25%)
0.161 0.276 0.065 0.315 0.941 0.362 0.771 0.692 0.147
22/21 (47.8%/45.7%) 18/25 (39.1%/54.3%)
4/8 (33.3%/66.7%) 9/2 (75%/16.7%)
0.443 0.043
9/37 (19.6%/80.4%)
1/11 (8.3%/91.7%)
0.670
2.5; 1.8e2.8 41/5 (89.1%/10.9%) 257; 144e528.5
3.1; 2.6e4 9/3 (75%/25%) 1515;368.5e5610.5
0.011 0.342 0.046
M/F, male/female; ALT, alanine aminotransferase; Alk-P, alkaline phosphatase; ICG-15R, indocyanine green dye retention rate at 15 minutes; PT-INR, prothrombin time international normalized ratio; HBsAg, hepatitis B serum antigen; HCV, hepatitis C virus; AFP, alpha-fetoprotein. a Continuous variables are expressed as median; 25 and 75 percentiles.
The results are comparable to previous studies conducted for systemic anti-angiogenic therapy, suggesting the applicability of AFP response for HCC patients after RFA. Change in tumour size and the amount of enhancing tissue in the treated area by contrast-enhanced imaging are recommended for evaluating treatment response for HCC patients undergoing non-surgical therapies.23,29 However, evaluating the size of contrast-enhanced area is subjective. Moreover, in the registration study of sorafenib for treating patients with advanced HCC, although tumour shrinkage was achieved in only 3% of patients, the overall survival significantly improved in patients treated with sorafenib.30 One recent study further demonstrated that a total of 16% of patients who achieved complete response after
Table 3 Factors of poor overall survival and recurrence for patients with a baseline serum alpha-fetoprotein (AFP) of 100 ng/ml and successful radiofrequency ablation (RFA) treatment by multivariate analysis. Variable Survival PT INR >1.1/1.1 Non-optimal/optimal AFP response Creatinine >1.5/1.5 mg/dl Recurrence Platelet 105/>105/mm3 Non-optimal/optimal AFP response Tumour size >2 cm/2 cm
Case Hazard 95% Confidence p-Value number ratio intervals 18/40 12/46
8.243 5.481
1.677e40.518 1.271e23.632
0.009 0.023
5/53
11.195 1.446e86.672
0.021
25/33 12/46
1.936 4.220
1.006e3.728 1.941e9.176
0.048 <0.001
38/20
2.360
1.100e5.062
0.027
PT-INR, prothrombin time international normalized ratio.
loco-regional therapies as per the EASL guidelines, which showed no enhancing tissue at CT, still had viable tumour in the subsequent pathological examination at liver transplantation or resection surgery.31 Thus, treatment response assessed by imaging studies is not perfect in patients treated by loco-regional therapy and chemotherapy. As AFP can be measured simply, rapidly, reliably, and objectively, the AFP response can be an ancillary tool for evaluating treatment response and predicting post-therapy prognosis for HCC patients undergoing RFA. In the present cohort, the impact of serum AFP levels on the prognosis of HCC patients after RFA therapy was demonstrated in two ways. First, patients with high baseline serum AFP levels had a significantly poorer overall survival and higher incidence of developing recurrence. Yamamoto et al.32 shows that higher serum AFP levels are associated with higher rates of vascular invasion, capsular infiltration, and poor tumour differentiation for HCC patients undergoing hepatectomy. The study suggests that serum AFP levels may also reflect tumour biology, thereby determining the prognosis of HCC patients after therapies. Second, in patients with baseline serum AFP levels of 100 ng/ml, a non-optimal AFP response is an independent poor prognostic factor, both in terms of survival and recurrence. This implies that monitoring serial serum AFP levels before and after therapy is mandatory for HCC patients undergoing RFA. In the present study, HCC patients with a non-optimal AFP response after RFA are older and have higher rates of chronic HCV infection, larger tumour sizes, and higher baseline AFP levels than those with an optimal AFP response. These patients may need closer monitoring for tumour recurrence after RFA therapy.
W.-Y. Kao et al. / Clinical Radiology 67 (2012) 429e436
The confirmation of RFA response in this study is determined by complete tumour necrosis 1 month after RFA therapy as demonstrated at CT or MRI.4 All patients with a non-optimal AFP response had tumour recurrence within 2 years after RFA, even though they initially achieved complete tumour necrosis after therapy, as shown by imaging studies. Consequently, clinicians should be more aware of the emergence of recurrence in patients with high baseline AFP values and a non-optimal AFP response after RFA therapy, which implies that residual, non-detectable tumours may be present. There may be two strategies for treating such patients: one is by closer monitoring using serial serum AFP levels and imaging, and the other is prescribing anti-tumour target therapy such as sorafenib. More large-scale, prospective studies are warranted to confirm this hypothesis. In the present cohort, most patients achieved complete tumour necrosis after one to two sessions of RFA therapy and only 14 patients (4.5%) had treatment failure. The latter patients had significantly larger tumour sizes than those with successful treatment (median tumour size 3.1 versus 2.2 cm). This result is consistent with previous studies.9,10,33e35 Baldan et al.33 demonstrated that the possibility of obtaining complete tumour ablation substantially decreases when the tumour size exceeds 3 cm. As such, for HCC patients with larger tumour sizes, a combination of treatment modalities may be warranted to improve the efficacy of RFA. In several retrospective studies and preliminary data of randomized, controlled trials, combining TACE with RFA has been shown to be more effective than RFA alone in terms of extending the ablated area and decreasing local tumour progression.34,36e38 However, the long-term outcomes between combination therapy and RFA alone for treating HCC of larger tumour size still needs to be elucidated with more prospective studies. The retrospective data analysis and small case numbers are the major limitations of the present study. Second, only a small proportion of patients with small HCC undergoing RFA had elevated serum AFP levels. More large-scale, prospective studies are warranted to confirm the application of AFP response in predicting prognosis after RFA. Third, beside AFP response, previous studies demonstrate that tumour biology and morphology also play important roles in determining the outcomes of HCC. Patients with well-defined encapsulated tumours have a higher rate of local tumour control after RFA or TACE and better prognosis than those with diffuse poorly marginated tumors.39e41 As this is a retrospective study, there were no detailed imaging characteristics or tumour biology before RFA; therefore, the efficacy of treatment and prognosis of patients by tumour morphology and biology could not be compared. In conclusion, the present study demonstrates that serum AFP response may be a useful marker for predicting prognosis in HCC patients undergoing RFA.
Acknowledgements This study was supported by grants from the National Science Council, Taiwan (97-2314-B-075-035, 98-2314-B-
435
075-030-MY2), Taipei Veterans General Hospital (V97A033, V98A-072, V98C1-120, V100A-034, V100C-034), and the Center of Excellence for Cancer Research at TVGH (DOH100-TD-C-111-007), Taipei, Taiwan. Writing assistance was provided by Gene Alzona Nisperos, MD.
Supplementary material Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.crad.2011.10. 009.
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