A
Multicenter
Randomized
Controlled
Trial
of
Percutaneous Cryoablation Versus Radiofrequency Ablation in Hepatocellular Carcinoma Chunping Wang1#, Huaming Wang2#，Wuwei Yang3#，Kaiwen Hu4#，Hui Xie2#， Ke-Qin Hu5, Wenlin Bai1, Zheng Dong1, Yinying Lu1, Zhen Zeng1, Min Lou1, Hong Wang1, Xudong Gao1, Xiujuan Chang1, Linjing An1, Jianhui Qu1, Jin Li6, Yongping Yang1* Emails of all authors: Chunping Wang: [email protected] Huaming Wang: [email protected] Wuwei Yang : [email protected] Kaiwen Hu:[email protected] Hui Xie: [email protected] Ke-Qin Hu :[email protected] Wenlin Bai: [email protected] Zheng Dong: [email protected] Yinying Lu: [email protected] Zhen Zeng: [email protected] Min Lou: [email protected] Hong Wang: [email protected] Xudong Gao: [email protected] Xiujuan Chang: [email protected] Linjing An: [email protected] Jianhui Qu: [email protected] Jin Li:[email protected] Yongping Yang: [email protected] 1. Center of Therapeutic Research for Hepatocellular Carcinoma, Beijing the 302nd
Hospital, Beijing, China 2. Center of Interventional Radiology for Oncology, Beijing the 302nd Hospital, Beijing, China 3. Center of Interventional Radiology for Oncology, the 307nd Affiliated Hospital of Military Academy of Sciences, Beijing, China. 4. Center of Oncology, Orient Affiliated Hospital of Beijing Traditional Chinese Medicine University, Beijing, China 5. Division of GI/Hepatology, University of California, Irvine, CA; and USA; This article has been accepted for publication and undergone full peer review but has not bee through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/hep.27548
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6. Medical Center, Beijing the 302nd Hospital, Beijing, China # These authors contributed equally to this work * To whom correspondence should be addressed: Yongping Yang, Center of Therapeutic Research for Hepatocellular Carcinoma, the 302nd Hospital, 100 Xi Si Huan Middle Road, Beijing 100039, China. Tel: +86-10-66933429; Fax: +86-10-63879193; E-mail address: [email protected]. Conflict of interest: The authors declare that there is no conflict of interest in this study.
Author Contributions Conception and design: Yongping Yang, Chunping Wang, Huaming Wang，Wuwei Yang，Kaiwen Hu, Ke-Qin Hu Study supervision: Yongping Yang, Huaming Wang，Wuwei Yang，Kaiwen Hu, Jin Li Financial support: Yongping Yang Manuscript writing and statistical analysis: Chunping Wang, Ke-Qin Hu, Yongping Yang Technica support(operator): Yongping Yang, Huaming Wang，Wuwei Yang， Kaiwen Hu Provision of study materials or patients: Huaming Wang，Wuwei Yang，Kaiwen Hu，Hui Xie，Wenlin Bai, Zheng Dong, Yinying Lu, Zhen Zeng, Min Lou, Hong Wang, Xudong Gao, Xiujuan Chang Collection and assembly of data: Hui Xie, Wuwei Yang，Kaiwen Hu， Zheng Dong, Linjing An, Jianhui Qu Data analysis and interpretation: Yongping Yang, Chunping Wang, Ke-Qin Hu Final approval of manuscript: Chunping Wang, Huaming Wang，Wuwei Yang， Kaiwen Hu，Hui Xie，Ke-Qin Hu, Wenlin Bai, Zheng Dong, Yinying Lu, Zhen Zeng, Min Lou, Hong Wang, Xudong Gao, Xiujuan Chang, Linjing An, Jianhui Qu, Jin Li, Yongping Yang
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Abstract
Radiofrequency ablation (RFA) is considered a curative treatment option for hepatocellular carcinoma (HCC). Growing data have demonstrated that cryoablation represents a safe and effective alternative therapy for HCC, but no randomization controlled trial (RCT) has been reported to compare cryoablation with RFA in HCC treatment. The present study was a multicenter RCT aimed to compare the outcomes of percutaneous cryoablation with RFA for the treatment of HCC. Three hundred and sixty patients with Child-Pugh class A or B cirrhosis and one or two HCC lesions ≤ 4 cm, treatment naïve, without metastasis were randomly assigned to cryoablation (n=180) or RFA (n=180). The primary end-points were local tumor progression at 3 years after treatment, and safety. Local tumor progression rates at 1, 2, and 3 years were 3%, 7%, and 7% for cryoablation and 9%, 11%, and 11% for RFA, respectively (P=0.043). For lesions >3 cm in diameter, local tumor progression rate was significantly lower in cryoablation group versus RFA group (7.7% vs 18.2%, P=0.041). The 1-, 3-, and 5-year overall survival rates were 97%, 67% and 40%, for cryoablation and 97%, 66%, and 38% for RFA, respectively (P=0.747). The 1-, 3-, and 5-year tumor-free survival rates were 89%, 54%, and 35% in cryoablation group and 84%, 50%, and 34% in
RFA
group,
respectively
(P=0.628).
Multivariate
analyses
demonstrated that Child-Pugh class B and distant intrahepatic recurrence were significant negative predictors to overall survival. Major 3
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complications occurred in seven patients (3.9%) following cryoablation and in six patients (3.3%) following RFA (P=0.776). Conclusion: Cryoablation resulted in a significantly lower local tumor progression, although both cryoablation and RFA were equally safe and effective with similar 5-year survival rates. Key words: Hepatocellular carcinoma; Cryoablation; Radiofrequency ablation; Randomized controlled trial; Safety
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Hepatocellular carcinoma
(HCC) is the sixth ranking cancer and the
third leading cause of cancer-related mortality globally.1 The incidence of HCC in China accounts for 55% of all HCC cases worldwide.2 Although hepatic resection remains a first-line treatment for HCC and orthotopic liver transplantation (OLT) offers high rates of disease-free remission, only 10–15% of HCC patients are suitable for hepatic resection or OLT. Therefore, percutaneous local ablative techniques including percutaneous ethanol injection (PEI), radiofrequency ablation (RFA), microwave (MV) and cryoablation (CRYO), have been the alternative options to unresectable HCC in cirrhotic patients.3
Percutaneous RFA is currently the most widely used ablation therapy for HCC due to its excellent local tumor control and acceptable morbidity3 and tumor seeding risk.4
Percutaneous cryoablation is a promising local ablation technique, which is believed to ablate cancer cells by several mechanisms including intracellular ice formation, solute-solvent shifts that cause cell dehydration and rupture, and small-vessel obliteration with resulting hypoxia.5 Perhaps, the main advantage of cryoablation relative to RFA is its precise intraprocedural monitoring of iceball formation via various imagings including computed tomography (CT),6 magnetic resonance 5
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imaging (MRI),7or ultrasound,8 therefore, optimally delivering the treatment effects.
Although some early review articles concluded that there was insufficient data to support or refute cryotherapy for HCC,9 many recent studies have shown that image-guided percutaneous cryoablation is safe and effective for HCC treatment.6,7,10,11 Our previous studies demonstrated that the rate of serious complications of percutaneous cryoablation was 6.3%11and the rate of tumor seeding was 0.76%.12Similar results were reported when compared RFA with surgical resection13, Li et al14 reported that percutaneous cryoablation and surgical resection were equally effective in the treating small, solitary HCC.
There are growing interests and application of percutaneous cryoablation for HCC treatment. However, there have been no randomization controlled trials (RCTs) to compare this modality with other ablation modalities, such as RFA.1 In this study, we conducted a prospective, multicenter RCT to compare cryoablation with RFA on their clinical outcomes in treating HCC patients with tumors ≤ 4 cm in diameter.
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Materials and Methods Study Concept. This was a prospective, multicenter, RCT conducted in three centers to compare the efficacy and safety of cryoablation (CRYO group) with RFA treatment (RFA group). The study met the requirements of the Declaration of Helsinki, and was approved by the Ethics Committee of each participating center, and was registered as a Chinese domestic clinical trial (20071203T) at the Clinicaltrial.gov in January 2008 in China.
Our previous study demonstrated that percutaneous cryotherapy could successfully ablate HCC tumors ≤ 5 cm in diameter.10 Despite the success of RFA for HCC smaller than 3cm, complete ablation rates for HCC larger than 3–5cm in diameter were reported at range from 61.3% to 82.5%.15,16However, Lin et al reported 96% complete ablation rate of RFA for HCC ≤ 4 cm.17 Based on these data, we chose patients with HCC ≤ 4 cm as the key inclusion criteria for this study. The primary end-points were local tumor progression (LTP) and safety. The secondary end-points were primary technique effectiveness rate, overall survival (OS), tumor-free survival (TFS) and distant tumor recurrence.
Sample Size. The sample size was based on the assumption that the cumulative LTP rate would be 12% in RFA group at the end of 1 year,17 7
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and would be 6% after cryoablation.10 Using Pass 2002 (NCSS, Kaysville, Utah, USA) statistical software, we calculated that approximately 180 patients including a drop-out rate of 5% would be required in each group to achieve a power of 0.80 and a significant level of 0.05 to assess the difference between the two groups.
Patients. HCC was diagnosed based on the criteria recommended by American Association for the Study of Liver Diseases (AASLD) or pathology.18,19 The cirrhosis had been diagnosed based on (1) a long history of chronic liver disease (hepatitis C virus (HCV), hepatitis B virus (HBV), alcoholic liver disease); (2) imaging features (evidence of nodular liver surface, caudate lobe hypertrophy, ‘‘coarse’’ liver tissue pattern and endoscopic findings (varices and/or portal hypertensive gastropathy) and (3) clinical evidence of portal hypertension,20 defined as the presence of esophagogastric varices and/or splenomegaly with platelet count lower than 100,000/mL, and/or history of ascites.18
The inclusion criteria for the present study included : (1) Diagnosis of HCC with tumor leision ≤ 4 cm and no more than two lesions; (2) no extrahepatic HCC metastases, or invasion of the portal vein, the hepatic vein trunk or secondary branches; (3) no previous HCC treatment; (4) underlying Child-Pugh class A or B cirrhosis; (5) no evidence of severe 8
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coagulopathy (ie, prolonged prothrombin time of > 5 seconds) or severe thrombocytopenia (ie, platelet count ≤ 40×109/L; (7) if ascites was diagnosed, it must be well controlled before enrollment (8) Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 2; Patients were excluded if any of the following conditions: (1) Patients who met the inclusion criteria, but declined to participate; (2) uncontrolled or refractory ascites, ongoing variceal bleeding, severe hypersplenism
syndrome
(ie,
platelet
count
≤
40×109/L)
or
encephalopathy; (3) Child–Pugh grade C cirrhosis; (4) HCC lesions beyond above inclusion, or located within 5 mm of the gallbladder, colon, stomach or the common bile duct; or (5) patients who preferred to receive surgery or OLT treatment.
From February 2008 to October 2013, 2426 consecutively registered patients with a diagnosis of HCC were admitted to one of those 3 hospitals for HCC treatment. All patients underwent a full and multidisciplinary evaluation to determine the treatment options, including cryoablation and RFA. For those who qualify the enrollment criteria, further discussion was provided to explain the study-related treatment and alternative options and invite their participation. A consent would then be obtained if a patient chose to participate. The Consort diagram for the study was shown in Figure 1. 9
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In 621/2426 patients who met the inclusion criteria, 205 with compensated cirrhosis received surgical resection, 21 with portal hypertension and decompensated cirrhosis received OLT, and 35 refused to participate, other 360 cirrhotic patients with HCC who chose to participate were enrolled in the study and randomly assigned at 1:1 ratio to cryoablation (n=180) and RFA (n=180). Among the 360 enrolled patients, 310 patients with significant portal hypertension were ineligible for surgical resection, the other 50 patients with Child-Pugh class A were considered to be suitable candidates for resection, but they declined this option. Of 1805/2426 patients who were excluded, 201 had more than 2 lesions, 342 had lesions over 4 cm in diameter, 202 had refractory ascites, 380 were Child–Pugh class C, 549 had vascular invasion, 88 had extrahepatic metastasis, 26 patients without cirrhosis received surgical resection and 17 patients with severe hypersplenism syndrome and hepatocellular dysfunction with the Model for End stage Liver Disease (MELD) Score ≥15 underwent OLT.
Randomization. Once enrolled, a consecutively numbered envelope was unsealed by a research assistant. The sealed numbers were generated by a computerized random number generator. Based on this number, the patient was randomly at 1:1 ratio assigned to the RFA group or 10
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cryoablation group.
Percutaneous Ablation Procedures. Both RFA and cryoablation were performed under local anesthesia on an inpatient basis by highly experienced physicians, who had performed RFA or cryoablation for over 500 patients. Before the procedures, pethidine 100 mg and antipsychotics 10 mg were given by intramuscular injection as basal sedation. For both procedures, a high-speed 16-slice spiral CT was used for guidance, localization, and intraoperative real-time ultrasound was used for monitoring of the ablation procedures to avoid ablated extension into surrounding critical structures.
Percutaneous Radiofrequency Ablation. Two different RFA devices were used in one center: 25 initial cases were done using the Elektrotom HiTT ablation system (Berchtold, Medizinelektronik, Germany), and 57 cases with the CelonLabPOWER System (Celon AG Olympus, Berlin, Germany) composed of a 470-kHz generator and internally cooled 16G applicators (CelonProSurge; Celon AG). In other two centers, RFA was performed only using the Elektrotom HiTT ablation system. The exposure times and energy deposition were followed according to the manufacturer’s standard instructions. The size of the needles and the
11
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number of exposures during any single session were determined on the basis of lesion size, location, and the expertise’s experience.
Percutaneous Cryoablation Device and Performamce. As shown in Figure 2, 4 or 8-cryoprobe surgery system (Endocare Corporation , Irvine, CA, USA), with superconducting cryoprobes in 2 or 3 mm in diameter and sheath-and-guidewire technique were used to perform cryoablation in the present study. Briefly, after sedation and preparation, an 18-gauge×15 cm PTC needle (Hakko Co. Ltd, Japan) was inserted to the tumor lesion under CT guidance, followed by super-stiff guidewire and a customized coaxial catheter introducer (Cordis Corporation, city, USA) that consists of dilation catheter and sheath, for cryoprobe insertion and instillation of hemostatic agents. An 8/11F coaxial coaxial catheter introducer was used to introduce cryoprobe and deliver cryotherapy. The procedure might be repeated if additional treatment was required. The location, number, and size of cryoprobes were determined according to the “2 to 1” principle by Wang H et al21to assure cryoprobes should be placed within 1 cm from the tumor edge, no more than 2 cm interval between the probes. Once all the cryoprobes had been placed, the cryosurgery system was initiated to begin rapid freezing. The temperature of the cryoprobes was decreased to -100˚C within 1 min, then further decreased and maintained between -150-160˚C for 20 min. After that, the heating system was 12
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initiated to re-warm the cryoprobes and the second cycle was repeated. Once these cycles were complete, the cryoprobes were withdrawn and a hemostatic gelatin sponge was tamped into the sheath in attempt to stop bleeding and fill the sinuses, and the sheath was then removed. The representative cryoablation images are shown in Figure. 3A.
Laboratory Data. Major biochemical and hematological variables including liver function and complete blood cell counts were collected and compared 1-4 days before, 1 day, and 14 days after the ablation treatment. Safety. The definition of a major complication was an event that led to substantial morbidity and mortality, or prolonged hospital stay. All other complications were considered minor including pain, post-ablation syndrome, asymptomatic pleural effusions, and minimal asymptomatic perihepatic fluid or blood collections found on imaging.22
Effectiveness and Follow-up. Four-phase helical contrast CT or contrast MRI was obtained within one week of the procedure to determine the extent of ablation. Patients with incomplete ablation were re-treated with the original procedure to completely ablate the tumor. All patients were followed and underwent serial monitoring of serum α-fetoprotein (AFP), chest CT scans, and abdominal CT or MRI scans every 3 months to detect 13
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tumor recurrence in the first year and then 6-monthly intervals thereafter. Patients with incomplete ablation after two sessions of the same technique, were considered treatment failures and those with LTP or distant tumor recurrence were further treated by PEI, MV, RFA, cryoablation, transcatheter arterial chemoembolization (TACE), sorafenib or surgery, as appropriate.
We defined primary technique effectiveness rate as percentage of tumors that were ablated completely following one or two session(s) of the treatment. LTP was defined as reappearance of tumor viable tissue within the ablation zone or less than 10mm from its borders. Distant intrahepatic tumor recurrence was defined as the appearance of HCC nodules in other hepatic segments or at a distance of greater than 10mm from the ablation zone.20,22 Extrahepatic metastases referred to any HCC localizated outside the liver parenchyma.
Statistical Analysis. Comparisons between groups were performed using the Student t test for continuous data and the χ2 test for categorical data. LTP and survival rates were estimated by the Kaplan-Meier method. Univariate and multivariate analyses were carried out using the Cox proportional hazards regression model. All variables with P 0.05).
Discussion In this study, the therapeutic efficacy of percutaneous cryoablation was compared with RFA in cirrhotic patients with HCC measuring ≤4 cm and no more than two tumors. No significant differences were observed in primary technique effectiveness rate, LTP, distant intrahepatic recurrence, complications, overall survival and tumor-free survival between the two groups. To the best of our knowledge, this is the largest prospective, multicenter randomized study to compare these two treatment modalities for the HCC.
Four previous nonrandomized studies compared the outcomes of cryoablation to RFA for hepatic malignancies including HCC and metastatic liver tumor (see supplement Table S1)23-26. Based on these studies, a meta-analysis concluded that RFA was significantly superior to cryoablation in complication and LTP.27 However, it should be noted that in
these studies, cryoablation was performed on different tumor types
including both HCC and metastatic liver tumors, and using equipment delivering liquid nitrogen as the coolant and laparoscopic or even intraoperative approaches, which have now been replaced by newer and 21
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safer generation of cryoablation devices and minimal invasive percutaneous approach. Additionally, growing clinical application of cryoablation has also improved operators’ experience and skill. Clearly, all these have contributed to improved efficacy and safety of the current cryoablation for HCC treatment. This notion has been supported by a recent retrospective study that reported similar safety of percutaneous cryoablation and RFA in the treating HCC in patients with cirrhosis.28
In the present study, there were no treatment-related mortality, renal insufficiency and coagulopathy in either group. The major complication rate following either treatment was comparable: 3.9% following cryoablation and 3.3% following RFA. Such low complication rate of cryoablation may be ascribed to the percutaneous approach and patients selection criteria. It had been reported that complications following cryoablation were related to the total ablation or freeze volume.10, 24Our results demonstrated that cryoablation of HCC lesions less than 4 cm is safe with reduced the risk of cryoshock, coagulation disorders, liver failure and myoglobinuria. Although cryoablation lacks an electrocautery needle tract as used in RFA, routine application of needle tract hemostatic technology and vascular sheath tamponade with hemostatic gelatin sponge during cryoablation may explain that no difference in the risk of bleeding was observed in both treatment arms. Peritoneal hemorrhage 22
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only occurred in 2 patients (1.1%) following cryoablation compared with 1 patient (0.6%) following RFA (P = 1.000). Another advantage of cryoablation is that it causes much less pain than RFA.
Our data demonstrated that these two treatment modalities were equally efficient in primary technique effectiveness rate and LTP in cirrhotic patients with HCC lesions ≤ 4 cm. The primary technique effectiveness rate was 98.3% in patients treated with cryoablation vs. 95.6% in those treated with RFA (P = 0.126). LTP following cryoablation was 5.6% and 10% following RFA (P = 0.1154). Such low LTP rates in our study may be related to the image-guided technology that ultrasound and CT were simultaneously used to guide the cryoprobe or RF applicator, which greatly improved the precision of probe localization, enhancing the safety and effectiveness of therapy. However, for tumors >3 cm, cryoablation was superior to RFA with respect to LTP and fewer treatment sessions. This may be attributed to the potential advantage of cryoablation over RFA in producing larger zones of ablation.29 In addition, cryoablation does not produce the “oven effect”, where heat is trapped within the tumor, as seen in RFA.29 The cryo-energy may be more conducive to clearance of micro-satellite lesions at the edge and surrounding of the tumor.29 This may explain why, in our study, the mean time for LTP was 9.8±4.7 months following cryoablation which occurred later than that of 23
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6.9±2.8 months following RAF, although no significant difference was found. Consistent with previous studies, tumor size was an independent factor associated with LTP.11,17, 20 We also showed that initial incomplete ablation was another factor related to LTP, similar to our previous study.10 A possible explanation for this may be related to the retreatment modalities for initial incomplete tumor ablation. Of 11 patients with initial incomplete ablation, 9 were treated with PEI, which has been reported to have a higher risk of LTP.30
With respect to long-term outcomes, there were no significant differences between the cryoablation and RFA groups in terms of 1-, 3-, and 5-year OS rates and of 1-, 3-, 5-year TFS. Consistent to previous reports,20 Child-Pugh class B was an independent negative prognostic factor for OS, irrespective of the ablation technique used. In addition, distant intrahepatic recurrence was identified as another significant factor related to OS, as previously reported.14,17 However, we failed to obtain significant factors related to TFS from baseline variables and cryoablation or RFA treatment. Tumor recurrence may be related to other factors, such as cirrhosis and intrahepatic inflammatory background, that would need further studies.
This study had the following limitations. First, the cirrhosis was based on 24
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clinical diagnosis. Second, the mean follow-up period was only 25 months. Judging from the overall and tumor-free survival curves, we do not think that there would be a significant difference in survival given a longer period of follow-up as the two treatment groups were almost exactly the same. Third, we did not analyze the difference in length of hospital stay, operating time and cost between the two groups. Finally, as our cohort included only HCC lesions ≤ 4 cm, we cannot extend our findings to HCC lesions beyond above criteria.
In conclusion, the present RCT demonstrated that in HCC patients with Child-Pugh class A-B cirrhosis, and HCC lesions ≤ 4 cm and no more than two lesions in total, percutaneous cryoablation and RFA are equally safe and effective ablation treatments. For HCC sized at 3.1–4.0 cm, percutaneous cryoablation is associated with a lower rate of LTP than RFA and should be considered as one of the standard local ablation modalities in these patients. References 1
2
3 4
European Association For The Study Of The Liver; European Organisation For Research And Treatment Of Cancer. EASL–EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol 2012;56:908-943. Yuen MF, Hou JL, Chutaputti A, Asia Pacific Working Party on Prevention of Hepatocellular Carcinoma. Hepatocellular carcinoma in the Asia–Pacific region. J Gastroenterol Hepatol 2009;24:346–353. Lencioni R. Loco-regional treatment of hepatocellular carcinoma. Hepatology 2010; 52:762–773 Stigliano R, Marelli L, Yu D, Davies N, Patch D, Burroughs AK.Seeding following percutaneous diagnostic and therapeutic approaches for hepatocellular 25
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5
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9 10
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14
15
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17
18
carcinoma. What is the risk and the outcome? Seeding risk for percutaneous approach of HCC. Cancer Treat Rev. 2007;33:437-447. Maccini M, Sehrt D, Pompeo A, Chicoli FA, Molina WR, Kim FJ. Biophysiologic considerations in cryoablation: a practical mechanistic molecular review. Int Braz J Urol. 2011;37:693-696. Orlacchio A, Bazzocchi G, Pastorelli D, Bolacchi F, Angelico M, Almerighi C, et al. Percutaneous cryoablation of small hepatocellular carcinoma with US guidance and CT monitoring: initial experience. Cardiovasc Intervent Radiol. 2008;31:587–594 Shimizu T, Sakuhara Y, Abo D, Hasegawa Y, Kodama Y, Endo H,et al. Outcome of MR-guided percutaneous cryoablation for hepatocellular carcinoma. J Hepatobiliary Pancreat Surg 2009;16: 816-823 Gilbert JC, Onik GM, Hoddick WK, Rubinsky B. Real time ultrasonic monitoring of hepatic cryosurgery. Gilbert JC, Onik GM, Hoddick WK, Rubinsky B.Cryobiology. 1985;22:319-330. Awad T, Thorlund K, Gluud C. Cryotherapy for hepatocellular carcinoma. Cochrane Database Syst Rev 2009;4:CD007611 Wang C, Lu Y, Chen Y, Feng Y, An L, Wang X,et al. Prognostic factors and recurrence of hepatitis B-related hepatocellular carcinoma after argon-helium cryoablation: a prospective study. Clin Exp Metastasis. 2009;26:839-848. Yang Y, Wang C, Lu Y, Bai W, An L, Qu J,et al. Outcomes of ultrasound-guided percutaneous argon-helium cryoablation of hepatocellular carcinoma. J Hepatobiliary Pancreat Sci. 2012;19:674-684. Wang C, Wang H, Qu J, Lu Y,Bai W, Dong D,et al. Tumour seeding after percutaneous cryoablation for hepatocellular carcinoma.World J Gastroenterol 2012;18: 6587-6596 Pompili M1, Saviano A, de Matthaeis N, Cucchetti A, Ardito F, Federico B, et al. Long-term effectiveness of resection and radiofrequency ablation for single hepatocellular carcinoma ≤3 cm. Results of a multicenter Italian survey. J Hepatol. 2013 ;59:89-97. Li Z, Zhang C, Lou C, Yan F, Mao Y, Hong X,et al. Comparison of percutaneous cryosurgery and surgical resection for the treatment of small hepatocellular carcinoma Oncol Lett 2013;6:239-245. Lupo L, Panzera P, Giannelli G, Memeo M, Gentile A, Memeo V. Single hepatocellular carcinoma ranging from 3 to 5 cm: radiofrequency ablation or resection? HPB (Oxford)2007;9:429–434. Harrison LE, Koneru B, Baramipour P, Fisher A, Barone A, Wilson D, et al. Locoregional recurrences are frequent after radiofrequency ablation for hepatocellular carcinoma. J Am Coll Surg 2003;197:759–764. Lin SM, Lin CJ, Lin CC, Hsu CW, Chen YC. Radiofrequency ablation improves prognosis compared with ethanol injection for hepatocellular carcinoma ≤4 cm. Gastroenterology2004;127:1714–1723 Bruix J, Sherman M. Management of hepatocellular carcinoma.Practice Guidelines Committee, American Association for the Study of Liver Diseases. Hepatology 2005;42:1208–1236. 26
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19 Bruix J, Sherman M; American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology. 2011 ;53:1020-1022. 20 Brunello F, Veltri A, Carucci P, Pagano E, Ciccone G, Moretto P,et al. Radiofrequency ablation versus ethanol injection for early hepatocellular carcinoma: A randomized controlled trial. Scandinavian J Gastroenterol 2008; 43: 727-735 21 Wang H, Littrup PJ, Duan Y, Zhang Y, Feng H, Nie Z. Thoracic masses treated with percutaneous cryotherapy: Initial experience with more than 200 procedures.Radiology.2005; 235:289-298 22 Goldberg SN, Grassi CJ, Cardella JF, Charboneau JW, Dodd GD 3rd, Dupuy DE, et al. Image-guided tumor ablation: standardization of terminology and reporting criteria. Radiology 2005;235: 728–739. 23 Pearson AS, Izzo F, Fleming RY, Ellis LM, Delrio P, Roh MS, et al.Intraoperative radiofrequency ablation or cryoablation for hepatic malignancies. Am J Surg. 1999;178:592-599. 24 Tait IS, Yong SM, Cuschieri SA. Laparoscopic in situ ablation of liver cancer with cryotherapy and radiofrequency ablation. Br J Surg. 2002;89:1613-1619. 25 Bilchik AJ, Wood TF, Allegra D, Tsioulias GJ, Chung M, Rose DM, et al. Cryosurgical ablation and radiofrequency ablation for unresectable hepatic malignant neoplasms: a proposed algorithm. Arch Surg. 2000;135:657-662; 26 Adam R, Hagopian EJ, Linhares M, Krissat J, Savier E, Azoulay D,et al. A comparison of percutaneous cryosurgery and percutaneous radiofrequency for unresectable hepatic malignancies. Arch Surg. 2002;137:1332-1339; 27 Huang YZ, Zhou SC, Zhou H, Tong M. Radiofrequency ablation versus cryosurgery ablation for hepatocellular carcinoma: a meta-analysis. Hepatogastroenterology. 2013 ;60:1131-1135 28 Dunne RM, Shyn PB, Sung JC, Tatli S, Morrison PR, Catalano PJ,et al. Percutaneous treatment of hepatocellular carcinoma in patients with cirrhosis: A comparison of the safety of cryoablation and radiofrequency ablation. Eur J Radiol. 2014;83:632-638. 29 Hinshaw JL, Lee FT Jr. Cryoablation for liver cancer. Tech Vasc Interv Radiol. 2007 ;10:47-57 30 Khan KN, Yatsuhashi H, Yamasaki K, Yamasaki M, Inoue O, Koga M, et al. Prospective analysis of risk factors for early intrahepatic recurrence of hepatocellular carcinoma following ethanol injection. J Hepatol 2000; 32:269–278
Fig. 1. Consort diagram for the study. Fig. 2. Percutaneous cryoablation of HCC described in detail. A: Dynamic contrast-enhanced MRI of the liver in a 51-year-old man with hepatitis B cirrhosis demonstrated a 2.2-cm HCC (see long arrow) in hepatic segment V, showing the typical enhancement pattern (arterial hypervascularization (a) followed by washout in the hepatic venous (b) and delayed (c) phase). Arrow head indicated a hemangioma. B: 27
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Summary of steps of technique of percutaneous cryotherapy for HCC and related CT images. (a) A percutaneous access needle was inserted into the tumor. (b) The super-stiff guidewire was inserted through the access needle. (c) The access needle was removed. (d) The 11F coaxial catheter introducers consisting of a dilation catheter (see black arrow) and sheath (see white arrow) were inserted into the tumor through the guidewire. (e) The guidewire and the dilation catheter were removed, and only the sheath was left in the tumor. (f) The cryoprobe (see black arrow) was inserted into the tumor through the sheath (see white arrow). Fig. 3. Cryoablation of HCC(A). a: MRI shows a HCC lesion 3.8 cm in diameter. b and c: Under CT guidance, two sheath-and guidewires were positioned in the tumor. d: MRI scanning two days after cryoablation of HCC. The HCC lesion was completely ablated showing a hypovascular zone with a hypervascular inflammatory rim around the ablation zone. e and f: MRI scanning at 6 months (e) and 12 months (f) after treatment shows that the ablated area had shrunk significantly. HCC recurrence after cryoablation(B) or RFA(C) .a :MRI show a HCC lesion with 3.0cm in diameter in cryoablation group and a HCC with 2.4cm in RFA group before treatment. b: MRI scanning at two days after cryoablation and RFA show the complete ablation of tumor. c: MRI image obtained 6 months after cryoablation or RFA show HCC recurrence at the periphery of the ablated lesion. D:Comparison of local tumor progression rate for tumor between cryoablation group and RFA group. Fig. 4. Cumulative survival curves for patients treated with cryoablation and RFA. (A) overall survival (log-rank test, χ2 = 0.104, P = 0.747), (B) tumor-free survival (log-rank test, χ2 = 0.235, P = 0.628) and the effects of Child-Pugh class (C) (log-rank test, χ2 = 10.852, P = 0.001) and distant intrahepatic recurrence (D) (log-rank test, χ2 = 98.912, P = 0.000) on overall survival.
28
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Table 1.
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Baseline characteristics of the study patients
Characteristics Age (mean ±SD) Gender(Male/Female) Etiology of cirrhosis HBV HCV HBV+HCV Alcoholic Child-Pugh classification A B Portal hypertension(present/absent) Serum AFP (ug/L) (mean ±SD) Tumor number 1 2 Tumor size (cm) ≤2 >2 and ≤4 Mean HBV DNA load (log10 IU/ml) Platelet count (× 109/L) (mean ± SD) ECOG 0 1 2 ALT(IU/L) (mean ± SD) AST(IU/L) (mean ± SD) Albumin (g/L) (mean ± SD) Bilirubin (µmol/L) (mean ± SD)
RFA group
CRYO group
(n = 180) 53.34±8.905 150/30
(n = 180) 53.87±9.587 140/40
163 12 3 2
170 8 2 0
109(60.56%) 71(39.44%) 162/18 211.3±580.2
121(67.22%) 59(32.78%) 148/32 268.1±823.7
171(95%) 9(5%)
161(89.44%) 19(10.56%)
P value NS NS NS
NS NS NS 0.04
NS 42(23.3%) 138(76.7%) 2.3±2.3 81.3±48.7
34(18.88%) 146(81.11%) 2.0±2.4 87.1±52.8
56(31.1%) 121(67.2%) 3(1.7%) 50.8±37.9 40.1±30.2 33.9±5.8 21.0±13.1
62(34.4%) 112(62.2%) 6(3.3%) 43.3±36.9 46.8±40.1 34.0±5.5 19.7±15.6
CRYO,cryoablation; AFP, α-fetoprotein; HBV, hepatitis B virus; HCV, hepatitis C virus; ECOG, Eastern Cooperative Oncology Group; PS, performance
status; ALT,
alanineaminotransferase; AST, aspartate aminotransferase; NS, not significant.
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NS NS NS
NS NS NS NS
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Table 2. Recurrence, overall survival and tumor-free survival of RFA and Cryoablation
Cryoablation(N=180)
RFA(N=180)
P value
Local recurrence
10 (5.6%)
18 (10%)
NS
New recurrence
56(31.1%)
54(30%)
NS
Overall survival
NS
1-year
97%
97%
3-year
67%
66%
5-year
40%
38% NS
Tumor-free survival 1-year
89%
84%
3-year
54%
50%
5-year
35%
34%
RFA: radiofrequency ablation; NS: not significant.
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Table 3.Univariate and multivariate analysis of local tumor progression Variable
Total tumor number
No. of local recurrence (%)
Univariate RR
95% CI
Multivariate P
RR
95% CI
P
2.093-46.766
0.019
Tumor Size ≤3 cm
220
9(4.09)
1
3.1-4 cm
168
21(12.5)
3.056
1 1.437-6.498
0.002
5.218
Complete ablation Complete ablation
377
26(6.90)
1
Incomplete ablation
11
4(36.36)
5.273
Nonspecial location
303
21(6.93)
1
Special location
85
9(10.59)
1.528
RFA
189
20(10.58)
1
Cryoablation
199
10(5.03)
0.475
1 2.219-12.516
0.002
5.278
1.24-22.39
0.024
0.727-3.211
0.265
1.051
0.306-1.776
0.725
0.201-1.748
0.677
Tumor location
Treatment 1 0.228-0.988
0.041
0.566
RR, risk ratio; CI, confidence interval; RFA, radiofrequency ablation. Special location referred to the area difficult to treat(adjacent to gallbladder(5), close to vena cava or portal vein(11),diaphragm dome(64),and caudate lobe(5)).
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Table 4. Univariate and multivariate analysis of the relative risk of overall survival. Univariate analysis
Multivariate analysis
Variable χ2 value (log-rank)
p value
Age (y) (≤54 vs. >54)
2.433
0.119
Sex(male vs. female)
2.042
0.153
HBV(yes vs.no)
0.256
0.613
HCV(yes vs.no)
0.036
0.850
RR (95% CI)
p value
Child-Pugh classification(A vs. B)
10.852
0.001
1.912(1.435-3.782)
0.018
Portal hypertension(yes vs. no)
5.560
0.021
1.531(0.782-3.683)
0.211
AFP (ng/ml) (≤20 vs. >20)
0.010
0.920
Tumor number (one vs. two)
4.337
0.037
1.233(0.776-4.251)
0.317
Tumor size (cm) (≤3 vs. >3 and 0 and≤2.0 >2.0
2.057
0.358
ECOG PS 0 1 2
0.129
0.938
Platelet (× 109/L) (≤76 vs. >76)
2.117
0.146
ALT (IU/L) (≤35 vs. >35)
0.798
0.372
AST (IU/L) (≤34 vs. >34)
0.450
0.502
Albumin (g/L) (≤33 vs. >33)
1.845
0.174
Bilirubin (µmol/L) (≤17 vs. >17)
1.272
0.259
Treatment(cryoablation vs. RFA)
0.104
0.747
1.187(0.724-2.451)
0.452
Distant intrahepatic recurrence
98.912
Multicenter
Randomized
Controlled
Trial
of
Percutaneous Cryoablation Versus Radiofrequency Ablation in Hepatocellular Carcinoma Chunping Wang1#, Huaming Wang2#，Wuwei Yang3#，Kaiwen Hu4#，Hui Xie2#， Ke-Qin Hu5, Wenlin Bai1, Zheng Dong1, Yinying Lu1, Zhen Zeng1, Min Lou1, Hong Wang1, Xudong Gao1, Xiujuan Chang1, Linjing An1, Jianhui Qu1, Jin Li6, Yongping Yang1* Emails of all authors: Chunping Wang: [email protected] Huaming Wang: [email protected] Wuwei Yang : [email protected] Kaiwen Hu:[email protected] Hui Xie: [email protected] Ke-Qin Hu :[email protected] Wenlin Bai: [email protected] Zheng Dong: [email protected] Yinying Lu: [email protected] Zhen Zeng: [email protected] Min Lou: [email protected] Hong Wang: [email protected] Xudong Gao: [email protected] Xiujuan Chang: [email protected] Linjing An: [email protected] Jianhui Qu: [email protected] Jin Li:[email protected] Yongping Yang: [email protected] 1. Center of Therapeutic Research for Hepatocellular Carcinoma, Beijing the 302nd
Hospital, Beijing, China 2. Center of Interventional Radiology for Oncology, Beijing the 302nd Hospital, Beijing, China 3. Center of Interventional Radiology for Oncology, the 307nd Affiliated Hospital of Military Academy of Sciences, Beijing, China. 4. Center of Oncology, Orient Affiliated Hospital of Beijing Traditional Chinese Medicine University, Beijing, China 5. Division of GI/Hepatology, University of California, Irvine, CA; and USA; This article has been accepted for publication and undergone full peer review but has not bee through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/hep.27548
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6. Medical Center, Beijing the 302nd Hospital, Beijing, China # These authors contributed equally to this work * To whom correspondence should be addressed: Yongping Yang, Center of Therapeutic Research for Hepatocellular Carcinoma, the 302nd Hospital, 100 Xi Si Huan Middle Road, Beijing 100039, China. Tel: +86-10-66933429; Fax: +86-10-63879193; E-mail address: [email protected]. Conflict of interest: The authors declare that there is no conflict of interest in this study.
Author Contributions Conception and design: Yongping Yang, Chunping Wang, Huaming Wang，Wuwei Yang，Kaiwen Hu, Ke-Qin Hu Study supervision: Yongping Yang, Huaming Wang，Wuwei Yang，Kaiwen Hu, Jin Li Financial support: Yongping Yang Manuscript writing and statistical analysis: Chunping Wang, Ke-Qin Hu, Yongping Yang Technica support(operator): Yongping Yang, Huaming Wang，Wuwei Yang， Kaiwen Hu Provision of study materials or patients: Huaming Wang，Wuwei Yang，Kaiwen Hu，Hui Xie，Wenlin Bai, Zheng Dong, Yinying Lu, Zhen Zeng, Min Lou, Hong Wang, Xudong Gao, Xiujuan Chang Collection and assembly of data: Hui Xie, Wuwei Yang，Kaiwen Hu， Zheng Dong, Linjing An, Jianhui Qu Data analysis and interpretation: Yongping Yang, Chunping Wang, Ke-Qin Hu Final approval of manuscript: Chunping Wang, Huaming Wang，Wuwei Yang， Kaiwen Hu，Hui Xie，Ke-Qin Hu, Wenlin Bai, Zheng Dong, Yinying Lu, Zhen Zeng, Min Lou, Hong Wang, Xudong Gao, Xiujuan Chang, Linjing An, Jianhui Qu, Jin Li, Yongping Yang
2
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Abstract
Radiofrequency ablation (RFA) is considered a curative treatment option for hepatocellular carcinoma (HCC). Growing data have demonstrated that cryoablation represents a safe and effective alternative therapy for HCC, but no randomization controlled trial (RCT) has been reported to compare cryoablation with RFA in HCC treatment. The present study was a multicenter RCT aimed to compare the outcomes of percutaneous cryoablation with RFA for the treatment of HCC. Three hundred and sixty patients with Child-Pugh class A or B cirrhosis and one or two HCC lesions ≤ 4 cm, treatment naïve, without metastasis were randomly assigned to cryoablation (n=180) or RFA (n=180). The primary end-points were local tumor progression at 3 years after treatment, and safety. Local tumor progression rates at 1, 2, and 3 years were 3%, 7%, and 7% for cryoablation and 9%, 11%, and 11% for RFA, respectively (P=0.043). For lesions >3 cm in diameter, local tumor progression rate was significantly lower in cryoablation group versus RFA group (7.7% vs 18.2%, P=0.041). The 1-, 3-, and 5-year overall survival rates were 97%, 67% and 40%, for cryoablation and 97%, 66%, and 38% for RFA, respectively (P=0.747). The 1-, 3-, and 5-year tumor-free survival rates were 89%, 54%, and 35% in cryoablation group and 84%, 50%, and 34% in
RFA
group,
respectively
(P=0.628).
Multivariate
analyses
demonstrated that Child-Pugh class B and distant intrahepatic recurrence were significant negative predictors to overall survival. Major 3
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complications occurred in seven patients (3.9%) following cryoablation and in six patients (3.3%) following RFA (P=0.776). Conclusion: Cryoablation resulted in a significantly lower local tumor progression, although both cryoablation and RFA were equally safe and effective with similar 5-year survival rates. Key words: Hepatocellular carcinoma; Cryoablation; Radiofrequency ablation; Randomized controlled trial; Safety
4
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Hepatocellular carcinoma
(HCC) is the sixth ranking cancer and the
third leading cause of cancer-related mortality globally.1 The incidence of HCC in China accounts for 55% of all HCC cases worldwide.2 Although hepatic resection remains a first-line treatment for HCC and orthotopic liver transplantation (OLT) offers high rates of disease-free remission, only 10–15% of HCC patients are suitable for hepatic resection or OLT. Therefore, percutaneous local ablative techniques including percutaneous ethanol injection (PEI), radiofrequency ablation (RFA), microwave (MV) and cryoablation (CRYO), have been the alternative options to unresectable HCC in cirrhotic patients.3
Percutaneous RFA is currently the most widely used ablation therapy for HCC due to its excellent local tumor control and acceptable morbidity3 and tumor seeding risk.4
Percutaneous cryoablation is a promising local ablation technique, which is believed to ablate cancer cells by several mechanisms including intracellular ice formation, solute-solvent shifts that cause cell dehydration and rupture, and small-vessel obliteration with resulting hypoxia.5 Perhaps, the main advantage of cryoablation relative to RFA is its precise intraprocedural monitoring of iceball formation via various imagings including computed tomography (CT),6 magnetic resonance 5
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imaging (MRI),7or ultrasound,8 therefore, optimally delivering the treatment effects.
Although some early review articles concluded that there was insufficient data to support or refute cryotherapy for HCC,9 many recent studies have shown that image-guided percutaneous cryoablation is safe and effective for HCC treatment.6,7,10,11 Our previous studies demonstrated that the rate of serious complications of percutaneous cryoablation was 6.3%11and the rate of tumor seeding was 0.76%.12Similar results were reported when compared RFA with surgical resection13, Li et al14 reported that percutaneous cryoablation and surgical resection were equally effective in the treating small, solitary HCC.
There are growing interests and application of percutaneous cryoablation for HCC treatment. However, there have been no randomization controlled trials (RCTs) to compare this modality with other ablation modalities, such as RFA.1 In this study, we conducted a prospective, multicenter RCT to compare cryoablation with RFA on their clinical outcomes in treating HCC patients with tumors ≤ 4 cm in diameter.
6
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Materials and Methods Study Concept. This was a prospective, multicenter, RCT conducted in three centers to compare the efficacy and safety of cryoablation (CRYO group) with RFA treatment (RFA group). The study met the requirements of the Declaration of Helsinki, and was approved by the Ethics Committee of each participating center, and was registered as a Chinese domestic clinical trial (20071203T) at the Clinicaltrial.gov in January 2008 in China.
Our previous study demonstrated that percutaneous cryotherapy could successfully ablate HCC tumors ≤ 5 cm in diameter.10 Despite the success of RFA for HCC smaller than 3cm, complete ablation rates for HCC larger than 3–5cm in diameter were reported at range from 61.3% to 82.5%.15,16However, Lin et al reported 96% complete ablation rate of RFA for HCC ≤ 4 cm.17 Based on these data, we chose patients with HCC ≤ 4 cm as the key inclusion criteria for this study. The primary end-points were local tumor progression (LTP) and safety. The secondary end-points were primary technique effectiveness rate, overall survival (OS), tumor-free survival (TFS) and distant tumor recurrence.
Sample Size. The sample size was based on the assumption that the cumulative LTP rate would be 12% in RFA group at the end of 1 year,17 7
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and would be 6% after cryoablation.10 Using Pass 2002 (NCSS, Kaysville, Utah, USA) statistical software, we calculated that approximately 180 patients including a drop-out rate of 5% would be required in each group to achieve a power of 0.80 and a significant level of 0.05 to assess the difference between the two groups.
Patients. HCC was diagnosed based on the criteria recommended by American Association for the Study of Liver Diseases (AASLD) or pathology.18,19 The cirrhosis had been diagnosed based on (1) a long history of chronic liver disease (hepatitis C virus (HCV), hepatitis B virus (HBV), alcoholic liver disease); (2) imaging features (evidence of nodular liver surface, caudate lobe hypertrophy, ‘‘coarse’’ liver tissue pattern and endoscopic findings (varices and/or portal hypertensive gastropathy) and (3) clinical evidence of portal hypertension,20 defined as the presence of esophagogastric varices and/or splenomegaly with platelet count lower than 100,000/mL, and/or history of ascites.18
The inclusion criteria for the present study included : (1) Diagnosis of HCC with tumor leision ≤ 4 cm and no more than two lesions; (2) no extrahepatic HCC metastases, or invasion of the portal vein, the hepatic vein trunk or secondary branches; (3) no previous HCC treatment; (4) underlying Child-Pugh class A or B cirrhosis; (5) no evidence of severe 8
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coagulopathy (ie, prolonged prothrombin time of > 5 seconds) or severe thrombocytopenia (ie, platelet count ≤ 40×109/L; (7) if ascites was diagnosed, it must be well controlled before enrollment (8) Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 2; Patients were excluded if any of the following conditions: (1) Patients who met the inclusion criteria, but declined to participate; (2) uncontrolled or refractory ascites, ongoing variceal bleeding, severe hypersplenism
syndrome
(ie,
platelet
count
≤
40×109/L)
or
encephalopathy; (3) Child–Pugh grade C cirrhosis; (4) HCC lesions beyond above inclusion, or located within 5 mm of the gallbladder, colon, stomach or the common bile duct; or (5) patients who preferred to receive surgery or OLT treatment.
From February 2008 to October 2013, 2426 consecutively registered patients with a diagnosis of HCC were admitted to one of those 3 hospitals for HCC treatment. All patients underwent a full and multidisciplinary evaluation to determine the treatment options, including cryoablation and RFA. For those who qualify the enrollment criteria, further discussion was provided to explain the study-related treatment and alternative options and invite their participation. A consent would then be obtained if a patient chose to participate. The Consort diagram for the study was shown in Figure 1. 9
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In 621/2426 patients who met the inclusion criteria, 205 with compensated cirrhosis received surgical resection, 21 with portal hypertension and decompensated cirrhosis received OLT, and 35 refused to participate, other 360 cirrhotic patients with HCC who chose to participate were enrolled in the study and randomly assigned at 1:1 ratio to cryoablation (n=180) and RFA (n=180). Among the 360 enrolled patients, 310 patients with significant portal hypertension were ineligible for surgical resection, the other 50 patients with Child-Pugh class A were considered to be suitable candidates for resection, but they declined this option. Of 1805/2426 patients who were excluded, 201 had more than 2 lesions, 342 had lesions over 4 cm in diameter, 202 had refractory ascites, 380 were Child–Pugh class C, 549 had vascular invasion, 88 had extrahepatic metastasis, 26 patients without cirrhosis received surgical resection and 17 patients with severe hypersplenism syndrome and hepatocellular dysfunction with the Model for End stage Liver Disease (MELD) Score ≥15 underwent OLT.
Randomization. Once enrolled, a consecutively numbered envelope was unsealed by a research assistant. The sealed numbers were generated by a computerized random number generator. Based on this number, the patient was randomly at 1:1 ratio assigned to the RFA group or 10
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cryoablation group.
Percutaneous Ablation Procedures. Both RFA and cryoablation were performed under local anesthesia on an inpatient basis by highly experienced physicians, who had performed RFA or cryoablation for over 500 patients. Before the procedures, pethidine 100 mg and antipsychotics 10 mg were given by intramuscular injection as basal sedation. For both procedures, a high-speed 16-slice spiral CT was used for guidance, localization, and intraoperative real-time ultrasound was used for monitoring of the ablation procedures to avoid ablated extension into surrounding critical structures.
Percutaneous Radiofrequency Ablation. Two different RFA devices were used in one center: 25 initial cases were done using the Elektrotom HiTT ablation system (Berchtold, Medizinelektronik, Germany), and 57 cases with the CelonLabPOWER System (Celon AG Olympus, Berlin, Germany) composed of a 470-kHz generator and internally cooled 16G applicators (CelonProSurge; Celon AG). In other two centers, RFA was performed only using the Elektrotom HiTT ablation system. The exposure times and energy deposition were followed according to the manufacturer’s standard instructions. The size of the needles and the
11
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number of exposures during any single session were determined on the basis of lesion size, location, and the expertise’s experience.
Percutaneous Cryoablation Device and Performamce. As shown in Figure 2, 4 or 8-cryoprobe surgery system (Endocare Corporation , Irvine, CA, USA), with superconducting cryoprobes in 2 or 3 mm in diameter and sheath-and-guidewire technique were used to perform cryoablation in the present study. Briefly, after sedation and preparation, an 18-gauge×15 cm PTC needle (Hakko Co. Ltd, Japan) was inserted to the tumor lesion under CT guidance, followed by super-stiff guidewire and a customized coaxial catheter introducer (Cordis Corporation, city, USA) that consists of dilation catheter and sheath, for cryoprobe insertion and instillation of hemostatic agents. An 8/11F coaxial coaxial catheter introducer was used to introduce cryoprobe and deliver cryotherapy. The procedure might be repeated if additional treatment was required. The location, number, and size of cryoprobes were determined according to the “2 to 1” principle by Wang H et al21to assure cryoprobes should be placed within 1 cm from the tumor edge, no more than 2 cm interval between the probes. Once all the cryoprobes had been placed, the cryosurgery system was initiated to begin rapid freezing. The temperature of the cryoprobes was decreased to -100˚C within 1 min, then further decreased and maintained between -150-160˚C for 20 min. After that, the heating system was 12
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initiated to re-warm the cryoprobes and the second cycle was repeated. Once these cycles were complete, the cryoprobes were withdrawn and a hemostatic gelatin sponge was tamped into the sheath in attempt to stop bleeding and fill the sinuses, and the sheath was then removed. The representative cryoablation images are shown in Figure. 3A.
Laboratory Data. Major biochemical and hematological variables including liver function and complete blood cell counts were collected and compared 1-4 days before, 1 day, and 14 days after the ablation treatment. Safety. The definition of a major complication was an event that led to substantial morbidity and mortality, or prolonged hospital stay. All other complications were considered minor including pain, post-ablation syndrome, asymptomatic pleural effusions, and minimal asymptomatic perihepatic fluid or blood collections found on imaging.22
Effectiveness and Follow-up. Four-phase helical contrast CT or contrast MRI was obtained within one week of the procedure to determine the extent of ablation. Patients with incomplete ablation were re-treated with the original procedure to completely ablate the tumor. All patients were followed and underwent serial monitoring of serum α-fetoprotein (AFP), chest CT scans, and abdominal CT or MRI scans every 3 months to detect 13
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tumor recurrence in the first year and then 6-monthly intervals thereafter. Patients with incomplete ablation after two sessions of the same technique, were considered treatment failures and those with LTP or distant tumor recurrence were further treated by PEI, MV, RFA, cryoablation, transcatheter arterial chemoembolization (TACE), sorafenib or surgery, as appropriate.
We defined primary technique effectiveness rate as percentage of tumors that were ablated completely following one or two session(s) of the treatment. LTP was defined as reappearance of tumor viable tissue within the ablation zone or less than 10mm from its borders. Distant intrahepatic tumor recurrence was defined as the appearance of HCC nodules in other hepatic segments or at a distance of greater than 10mm from the ablation zone.20,22 Extrahepatic metastases referred to any HCC localizated outside the liver parenchyma.
Statistical Analysis. Comparisons between groups were performed using the Student t test for continuous data and the χ2 test for categorical data. LTP and survival rates were estimated by the Kaplan-Meier method. Univariate and multivariate analyses were carried out using the Cox proportional hazards regression model. All variables with P 0.05).
Discussion In this study, the therapeutic efficacy of percutaneous cryoablation was compared with RFA in cirrhotic patients with HCC measuring ≤4 cm and no more than two tumors. No significant differences were observed in primary technique effectiveness rate, LTP, distant intrahepatic recurrence, complications, overall survival and tumor-free survival between the two groups. To the best of our knowledge, this is the largest prospective, multicenter randomized study to compare these two treatment modalities for the HCC.
Four previous nonrandomized studies compared the outcomes of cryoablation to RFA for hepatic malignancies including HCC and metastatic liver tumor (see supplement Table S1)23-26. Based on these studies, a meta-analysis concluded that RFA was significantly superior to cryoablation in complication and LTP.27 However, it should be noted that in
these studies, cryoablation was performed on different tumor types
including both HCC and metastatic liver tumors, and using equipment delivering liquid nitrogen as the coolant and laparoscopic or even intraoperative approaches, which have now been replaced by newer and 21
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safer generation of cryoablation devices and minimal invasive percutaneous approach. Additionally, growing clinical application of cryoablation has also improved operators’ experience and skill. Clearly, all these have contributed to improved efficacy and safety of the current cryoablation for HCC treatment. This notion has been supported by a recent retrospective study that reported similar safety of percutaneous cryoablation and RFA in the treating HCC in patients with cirrhosis.28
In the present study, there were no treatment-related mortality, renal insufficiency and coagulopathy in either group. The major complication rate following either treatment was comparable: 3.9% following cryoablation and 3.3% following RFA. Such low complication rate of cryoablation may be ascribed to the percutaneous approach and patients selection criteria. It had been reported that complications following cryoablation were related to the total ablation or freeze volume.10, 24Our results demonstrated that cryoablation of HCC lesions less than 4 cm is safe with reduced the risk of cryoshock, coagulation disorders, liver failure and myoglobinuria. Although cryoablation lacks an electrocautery needle tract as used in RFA, routine application of needle tract hemostatic technology and vascular sheath tamponade with hemostatic gelatin sponge during cryoablation may explain that no difference in the risk of bleeding was observed in both treatment arms. Peritoneal hemorrhage 22
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only occurred in 2 patients (1.1%) following cryoablation compared with 1 patient (0.6%) following RFA (P = 1.000). Another advantage of cryoablation is that it causes much less pain than RFA.
Our data demonstrated that these two treatment modalities were equally efficient in primary technique effectiveness rate and LTP in cirrhotic patients with HCC lesions ≤ 4 cm. The primary technique effectiveness rate was 98.3% in patients treated with cryoablation vs. 95.6% in those treated with RFA (P = 0.126). LTP following cryoablation was 5.6% and 10% following RFA (P = 0.1154). Such low LTP rates in our study may be related to the image-guided technology that ultrasound and CT were simultaneously used to guide the cryoprobe or RF applicator, which greatly improved the precision of probe localization, enhancing the safety and effectiveness of therapy. However, for tumors >3 cm, cryoablation was superior to RFA with respect to LTP and fewer treatment sessions. This may be attributed to the potential advantage of cryoablation over RFA in producing larger zones of ablation.29 In addition, cryoablation does not produce the “oven effect”, where heat is trapped within the tumor, as seen in RFA.29 The cryo-energy may be more conducive to clearance of micro-satellite lesions at the edge and surrounding of the tumor.29 This may explain why, in our study, the mean time for LTP was 9.8±4.7 months following cryoablation which occurred later than that of 23
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6.9±2.8 months following RAF, although no significant difference was found. Consistent with previous studies, tumor size was an independent factor associated with LTP.11,17, 20 We also showed that initial incomplete ablation was another factor related to LTP, similar to our previous study.10 A possible explanation for this may be related to the retreatment modalities for initial incomplete tumor ablation. Of 11 patients with initial incomplete ablation, 9 were treated with PEI, which has been reported to have a higher risk of LTP.30
With respect to long-term outcomes, there were no significant differences between the cryoablation and RFA groups in terms of 1-, 3-, and 5-year OS rates and of 1-, 3-, 5-year TFS. Consistent to previous reports,20 Child-Pugh class B was an independent negative prognostic factor for OS, irrespective of the ablation technique used. In addition, distant intrahepatic recurrence was identified as another significant factor related to OS, as previously reported.14,17 However, we failed to obtain significant factors related to TFS from baseline variables and cryoablation or RFA treatment. Tumor recurrence may be related to other factors, such as cirrhosis and intrahepatic inflammatory background, that would need further studies.
This study had the following limitations. First, the cirrhosis was based on 24
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clinical diagnosis. Second, the mean follow-up period was only 25 months. Judging from the overall and tumor-free survival curves, we do not think that there would be a significant difference in survival given a longer period of follow-up as the two treatment groups were almost exactly the same. Third, we did not analyze the difference in length of hospital stay, operating time and cost between the two groups. Finally, as our cohort included only HCC lesions ≤ 4 cm, we cannot extend our findings to HCC lesions beyond above criteria.
In conclusion, the present RCT demonstrated that in HCC patients with Child-Pugh class A-B cirrhosis, and HCC lesions ≤ 4 cm and no more than two lesions in total, percutaneous cryoablation and RFA are equally safe and effective ablation treatments. For HCC sized at 3.1–4.0 cm, percutaneous cryoablation is associated with a lower rate of LTP than RFA and should be considered as one of the standard local ablation modalities in these patients. References 1
2
3 4
European Association For The Study Of The Liver; European Organisation For Research And Treatment Of Cancer. EASL–EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol 2012;56:908-943. Yuen MF, Hou JL, Chutaputti A, Asia Pacific Working Party on Prevention of Hepatocellular Carcinoma. Hepatocellular carcinoma in the Asia–Pacific region. J Gastroenterol Hepatol 2009;24:346–353. Lencioni R. Loco-regional treatment of hepatocellular carcinoma. Hepatology 2010; 52:762–773 Stigliano R, Marelli L, Yu D, Davies N, Patch D, Burroughs AK.Seeding following percutaneous diagnostic and therapeutic approaches for hepatocellular 25
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carcinoma. What is the risk and the outcome? Seeding risk for percutaneous approach of HCC. Cancer Treat Rev. 2007;33:437-447. Maccini M, Sehrt D, Pompeo A, Chicoli FA, Molina WR, Kim FJ. Biophysiologic considerations in cryoablation: a practical mechanistic molecular review. Int Braz J Urol. 2011;37:693-696. Orlacchio A, Bazzocchi G, Pastorelli D, Bolacchi F, Angelico M, Almerighi C, et al. Percutaneous cryoablation of small hepatocellular carcinoma with US guidance and CT monitoring: initial experience. Cardiovasc Intervent Radiol. 2008;31:587–594 Shimizu T, Sakuhara Y, Abo D, Hasegawa Y, Kodama Y, Endo H,et al. Outcome of MR-guided percutaneous cryoablation for hepatocellular carcinoma. J Hepatobiliary Pancreat Surg 2009;16: 816-823 Gilbert JC, Onik GM, Hoddick WK, Rubinsky B. Real time ultrasonic monitoring of hepatic cryosurgery. Gilbert JC, Onik GM, Hoddick WK, Rubinsky B.Cryobiology. 1985;22:319-330. Awad T, Thorlund K, Gluud C. Cryotherapy for hepatocellular carcinoma. Cochrane Database Syst Rev 2009;4:CD007611 Wang C, Lu Y, Chen Y, Feng Y, An L, Wang X,et al. Prognostic factors and recurrence of hepatitis B-related hepatocellular carcinoma after argon-helium cryoablation: a prospective study. Clin Exp Metastasis. 2009;26:839-848. Yang Y, Wang C, Lu Y, Bai W, An L, Qu J,et al. Outcomes of ultrasound-guided percutaneous argon-helium cryoablation of hepatocellular carcinoma. J Hepatobiliary Pancreat Sci. 2012;19:674-684. Wang C, Wang H, Qu J, Lu Y,Bai W, Dong D,et al. Tumour seeding after percutaneous cryoablation for hepatocellular carcinoma.World J Gastroenterol 2012;18: 6587-6596 Pompili M1, Saviano A, de Matthaeis N, Cucchetti A, Ardito F, Federico B, et al. Long-term effectiveness of resection and radiofrequency ablation for single hepatocellular carcinoma ≤3 cm. Results of a multicenter Italian survey. J Hepatol. 2013 ;59:89-97. Li Z, Zhang C, Lou C, Yan F, Mao Y, Hong X,et al. Comparison of percutaneous cryosurgery and surgical resection for the treatment of small hepatocellular carcinoma Oncol Lett 2013;6:239-245. Lupo L, Panzera P, Giannelli G, Memeo M, Gentile A, Memeo V. Single hepatocellular carcinoma ranging from 3 to 5 cm: radiofrequency ablation or resection? HPB (Oxford)2007;9:429–434. Harrison LE, Koneru B, Baramipour P, Fisher A, Barone A, Wilson D, et al. Locoregional recurrences are frequent after radiofrequency ablation for hepatocellular carcinoma. J Am Coll Surg 2003;197:759–764. Lin SM, Lin CJ, Lin CC, Hsu CW, Chen YC. Radiofrequency ablation improves prognosis compared with ethanol injection for hepatocellular carcinoma ≤4 cm. Gastroenterology2004;127:1714–1723 Bruix J, Sherman M. Management of hepatocellular carcinoma.Practice Guidelines Committee, American Association for the Study of Liver Diseases. Hepatology 2005;42:1208–1236. 26
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19 Bruix J, Sherman M; American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology. 2011 ;53:1020-1022. 20 Brunello F, Veltri A, Carucci P, Pagano E, Ciccone G, Moretto P,et al. Radiofrequency ablation versus ethanol injection for early hepatocellular carcinoma: A randomized controlled trial. Scandinavian J Gastroenterol 2008; 43: 727-735 21 Wang H, Littrup PJ, Duan Y, Zhang Y, Feng H, Nie Z. Thoracic masses treated with percutaneous cryotherapy: Initial experience with more than 200 procedures.Radiology.2005; 235:289-298 22 Goldberg SN, Grassi CJ, Cardella JF, Charboneau JW, Dodd GD 3rd, Dupuy DE, et al. Image-guided tumor ablation: standardization of terminology and reporting criteria. Radiology 2005;235: 728–739. 23 Pearson AS, Izzo F, Fleming RY, Ellis LM, Delrio P, Roh MS, et al.Intraoperative radiofrequency ablation or cryoablation for hepatic malignancies. Am J Surg. 1999;178:592-599. 24 Tait IS, Yong SM, Cuschieri SA. Laparoscopic in situ ablation of liver cancer with cryotherapy and radiofrequency ablation. Br J Surg. 2002;89:1613-1619. 25 Bilchik AJ, Wood TF, Allegra D, Tsioulias GJ, Chung M, Rose DM, et al. Cryosurgical ablation and radiofrequency ablation for unresectable hepatic malignant neoplasms: a proposed algorithm. Arch Surg. 2000;135:657-662; 26 Adam R, Hagopian EJ, Linhares M, Krissat J, Savier E, Azoulay D,et al. A comparison of percutaneous cryosurgery and percutaneous radiofrequency for unresectable hepatic malignancies. Arch Surg. 2002;137:1332-1339; 27 Huang YZ, Zhou SC, Zhou H, Tong M. Radiofrequency ablation versus cryosurgery ablation for hepatocellular carcinoma: a meta-analysis. Hepatogastroenterology. 2013 ;60:1131-1135 28 Dunne RM, Shyn PB, Sung JC, Tatli S, Morrison PR, Catalano PJ,et al. Percutaneous treatment of hepatocellular carcinoma in patients with cirrhosis: A comparison of the safety of cryoablation and radiofrequency ablation. Eur J Radiol. 2014;83:632-638. 29 Hinshaw JL, Lee FT Jr. Cryoablation for liver cancer. Tech Vasc Interv Radiol. 2007 ;10:47-57 30 Khan KN, Yatsuhashi H, Yamasaki K, Yamasaki M, Inoue O, Koga M, et al. Prospective analysis of risk factors for early intrahepatic recurrence of hepatocellular carcinoma following ethanol injection. J Hepatol 2000; 32:269–278
Fig. 1. Consort diagram for the study. Fig. 2. Percutaneous cryoablation of HCC described in detail. A: Dynamic contrast-enhanced MRI of the liver in a 51-year-old man with hepatitis B cirrhosis demonstrated a 2.2-cm HCC (see long arrow) in hepatic segment V, showing the typical enhancement pattern (arterial hypervascularization (a) followed by washout in the hepatic venous (b) and delayed (c) phase). Arrow head indicated a hemangioma. B: 27
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Summary of steps of technique of percutaneous cryotherapy for HCC and related CT images. (a) A percutaneous access needle was inserted into the tumor. (b) The super-stiff guidewire was inserted through the access needle. (c) The access needle was removed. (d) The 11F coaxial catheter introducers consisting of a dilation catheter (see black arrow) and sheath (see white arrow) were inserted into the tumor through the guidewire. (e) The guidewire and the dilation catheter were removed, and only the sheath was left in the tumor. (f) The cryoprobe (see black arrow) was inserted into the tumor through the sheath (see white arrow). Fig. 3. Cryoablation of HCC(A). a: MRI shows a HCC lesion 3.8 cm in diameter. b and c: Under CT guidance, two sheath-and guidewires were positioned in the tumor. d: MRI scanning two days after cryoablation of HCC. The HCC lesion was completely ablated showing a hypovascular zone with a hypervascular inflammatory rim around the ablation zone. e and f: MRI scanning at 6 months (e) and 12 months (f) after treatment shows that the ablated area had shrunk significantly. HCC recurrence after cryoablation(B) or RFA(C) .a :MRI show a HCC lesion with 3.0cm in diameter in cryoablation group and a HCC with 2.4cm in RFA group before treatment. b: MRI scanning at two days after cryoablation and RFA show the complete ablation of tumor. c: MRI image obtained 6 months after cryoablation or RFA show HCC recurrence at the periphery of the ablated lesion. D:Comparison of local tumor progression rate for tumor between cryoablation group and RFA group. Fig. 4. Cumulative survival curves for patients treated with cryoablation and RFA. (A) overall survival (log-rank test, χ2 = 0.104, P = 0.747), (B) tumor-free survival (log-rank test, χ2 = 0.235, P = 0.628) and the effects of Child-Pugh class (C) (log-rank test, χ2 = 10.852, P = 0.001) and distant intrahepatic recurrence (D) (log-rank test, χ2 = 98.912, P = 0.000) on overall survival.
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Table 1.
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Baseline characteristics of the study patients
Characteristics Age (mean ±SD) Gender(Male/Female) Etiology of cirrhosis HBV HCV HBV+HCV Alcoholic Child-Pugh classification A B Portal hypertension(present/absent) Serum AFP (ug/L) (mean ±SD) Tumor number 1 2 Tumor size (cm) ≤2 >2 and ≤4 Mean HBV DNA load (log10 IU/ml) Platelet count (× 109/L) (mean ± SD) ECOG 0 1 2 ALT(IU/L) (mean ± SD) AST(IU/L) (mean ± SD) Albumin (g/L) (mean ± SD) Bilirubin (µmol/L) (mean ± SD)
RFA group
CRYO group
(n = 180) 53.34±8.905 150/30
(n = 180) 53.87±9.587 140/40
163 12 3 2
170 8 2 0
109(60.56%) 71(39.44%) 162/18 211.3±580.2
121(67.22%) 59(32.78%) 148/32 268.1±823.7
171(95%) 9(5%)
161(89.44%) 19(10.56%)
P value NS NS NS
NS NS NS 0.04
NS 42(23.3%) 138(76.7%) 2.3±2.3 81.3±48.7
34(18.88%) 146(81.11%) 2.0±2.4 87.1±52.8
56(31.1%) 121(67.2%) 3(1.7%) 50.8±37.9 40.1±30.2 33.9±5.8 21.0±13.1
62(34.4%) 112(62.2%) 6(3.3%) 43.3±36.9 46.8±40.1 34.0±5.5 19.7±15.6
CRYO,cryoablation; AFP, α-fetoprotein; HBV, hepatitis B virus; HCV, hepatitis C virus; ECOG, Eastern Cooperative Oncology Group; PS, performance
status; ALT,
alanineaminotransferase; AST, aspartate aminotransferase; NS, not significant.
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NS NS NS
NS NS NS NS
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Table 2. Recurrence, overall survival and tumor-free survival of RFA and Cryoablation
Cryoablation(N=180)
RFA(N=180)
P value
Local recurrence
10 (5.6%)
18 (10%)
NS
New recurrence
56(31.1%)
54(30%)
NS
Overall survival
NS
1-year
97%
97%
3-year
67%
66%
5-year
40%
38% NS
Tumor-free survival 1-year
89%
84%
3-year
54%
50%
5-year
35%
34%
RFA: radiofrequency ablation; NS: not significant.
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Table 3.Univariate and multivariate analysis of local tumor progression Variable
Total tumor number
No. of local recurrence (%)
Univariate RR
95% CI
Multivariate P
RR
95% CI
P
2.093-46.766
0.019
Tumor Size ≤3 cm
220
9(4.09)
1
3.1-4 cm
168
21(12.5)
3.056
1 1.437-6.498
0.002
5.218
Complete ablation Complete ablation
377
26(6.90)
1
Incomplete ablation
11
4(36.36)
5.273
Nonspecial location
303
21(6.93)
1
Special location
85
9(10.59)
1.528
RFA
189
20(10.58)
1
Cryoablation
199
10(5.03)
0.475
1 2.219-12.516
0.002
5.278
1.24-22.39
0.024
0.727-3.211
0.265
1.051
0.306-1.776
0.725
0.201-1.748
0.677
Tumor location
Treatment 1 0.228-0.988
0.041
0.566
RR, risk ratio; CI, confidence interval; RFA, radiofrequency ablation. Special location referred to the area difficult to treat(adjacent to gallbladder(5), close to vena cava or portal vein(11),diaphragm dome(64),and caudate lobe(5)).
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Table 4. Univariate and multivariate analysis of the relative risk of overall survival. Univariate analysis
Multivariate analysis
Variable χ2 value (log-rank)
p value
Age (y) (≤54 vs. >54)
2.433
0.119
Sex(male vs. female)
2.042
0.153
HBV(yes vs.no)
0.256
0.613
HCV(yes vs.no)
0.036
0.850
RR (95% CI)
p value
Child-Pugh classification(A vs. B)
10.852
0.001
1.912(1.435-3.782)
0.018
Portal hypertension(yes vs. no)
5.560
0.021
1.531(0.782-3.683)
0.211
AFP (ng/ml) (≤20 vs. >20)
0.010
0.920
Tumor number (one vs. two)
4.337
0.037
1.233(0.776-4.251)
0.317
Tumor size (cm) (≤3 vs. >3 and 0 and≤2.0 >2.0
2.057
0.358
ECOG PS 0 1 2
0.129
0.938
Platelet (× 109/L) (≤76 vs. >76)
2.117
0.146
ALT (IU/L) (≤35 vs. >35)
0.798
0.372
AST (IU/L) (≤34 vs. >34)
0.450
0.502
Albumin (g/L) (≤33 vs. >33)
1.845
0.174
Bilirubin (µmol/L) (≤17 vs. >17)
1.272
0.259
Treatment(cryoablation vs. RFA)
0.104
0.747
1.187(0.724-2.451)
0.452
Distant intrahepatic recurrence
98.912
