1 Taipei Veterans General Hospital, Division of Gastroenterology, Department of Medicine, Taipei, Taiwan; 2 National Yang-Ming University School of Medicine, Faculty of Medicine, Taipei, Taiwan, Republic of China
Received 21 November 2003; revised 19 January 2004; accepted 21 January 2004
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ABSTRACT |
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Transarterial chemoembolization (TACE) and percutaneous acetic acid injection (PAI) are effective locoregional therapies for hepatocellular carcinoma (HCC). This study aimed to investigate whether HCC patients who had initial complete response to these treatments had a subsequent lower risk of intrahepatic metastasis.
Patients and methods:
A total of 152 patients who underwent locoregional therapy (94 received PAI and 58 received both TACE and PAI) for HCC (tumor size 5 cm) were prospectively evaluated.
Results:
In all, 60 (39%) patients had a complete tumor necrosis after treatment. The cumulative incidence of the development of intrahepatic metastasis was lower for patients with complete remission (P = 0.005) and for patients with smaller (3 cm) tumor size (P = 0.083). Cox multivariate survival analysis showed that absence of complete remission [relative risk (RR) 2.7; 95% confidence interval (CI) 1.45.3; P = 0.003] was the only independent factor that predicted the occurrence of intrahepatic metastasis. Patients with complete remission had a significantly better long-term survival than those without (P = 0.002), and the occurrence of intrahepatic metastasis over time independently predicted a decreased survival (RR 3.2; 95% CI 2.06.1; P = 0.019).
Conclusions:
Induction of complete tumor necrosis in HCC patients undergoing locoregional therapy may decrease the risk of intrahepatic metastasis and improve survival.
Key words: arterial embolization, hepatocellular carcinoma, liver cirrhosis, metastasis, percutaneous acetic acid injection
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Introduction |
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For patients with unresectable disease, the goal of palliative locoregional therapy is to control symptoms and prolong survival [7, 11, 25]. TACE using iodized oil and chemotherapeutic agents combines the effect of targeted chemotherapy with that of ischemic necrosis induced by arterial embolization. It can be administered repeatedly, and can prolong survival in patients with unresectable hypervascular HCC [7, 11, 25, 26]. Alternatively, some reports have suggested that by using 1550% acetic acid, percutaneous acetic acid injection (PAI) has stronger necrotizing power than that of pure ethanol [20, 21], and may be equally effective as, or even superior to, ethanol injection in treating small HCC [19, 22]. However, given the above available treatment options, the induction of complete tumor necrosis after initial treatment to enter into a tumor-free status may be difficult to achieve, especially for those with large HCCs. Persistently viable (not completely ablated) tumors can show progressive neoplastic changes and facilitate intrahepatic metastasis, which has been considered a poor prognostic factor and may further increase the difficulty of managing the cancer [8, 22]. To determine the therapeutic significance of complete treatment response after locoregional therapy in patients with unresectable disease, in this study we have prospectively investigated whether the induction of complete response in HCC patients undergoing PAI alone or in combination with TACE may decrease the risk of intrahepatic metastasis and its prognostic impact on the long-term survival.
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Patients and methods |
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Treatment and follow-up
TACE was carried out according to Seldingers technique for arterial embolization [30, 31]. The equipment for selective common or proper hepatic artery angiography was LCN (GE Medical Systems, Waukesha, WI, USA) or Diagnost 3 (Philips, Amsterdam, The Netherlands). Hepatic arteriography and superior mesenteric arterial portovenography were performed to define the size and location of tumor nodules. During the sequential scanning of the liver, 100150 ml radiocontrast medium (Telebrix; Laboratoire Guerbet, Aulnay-Sous-Bois, France or Ultravist, Schering, Berlin, Germany) was injected using a power injector (CT9000 ADV; Liebel-Flarsheim, St Louis, MO, USA) to evaluate the vascularity of the tumor (tumor stain). The arteries supplying the tumor were catheterized superselectively, followed by infusion of a mixture of 2030 mg adriamycin (Carlo Erba, Milan, Italy) and 510 ml Lipiodol (Laboratoire Guerbet). The aim was to deliver a sufficient amount of emulsion to the tumoral areas without retrograde flow. Under fluoroscopic control, the feeding arteries were subsequently embolized with 23 mm strips of Gelfoam (Upjohn, Kalamazoo, MI, USA) until complete flow stagnation was achieved.
The equipment used for PAI was a commercially available ultrasound scanner, with a puncture probe with guide device (Aloka, Tokyo, Japan). Sterile 50% acetic acid (Merck, Darmstadt, Germany) was injected with a 22-gauge spinal needle [22, 31]. Treatment was administered twice a week in an in-patient setting. Typically, one or two injections at a dose of 24 ml acetic acid were given during each treatment session. Acetic acid was slowly injected until the echogenic area appearing immediately after injection covered the entire tumor. After the injection was complete, the needle was left in place for 1 min to prevent reflux of acetic acid into peritoneal cavity. Two to four sessions were given for the lesions <3 cm in size and four to five sessions were given for the lesions between 3 and 5 cm. For patients with multiple tumors, PAI was performed first on the main tumor (the one with the largest diameter), followed by treating the smaller ones until all tumors were successfully treated.
A total of 166 patients were prospectively enrolled; none of them had undergone specific anticancer treatment before enrollment. Sixty-three patients received combination therapy of TACE and PAI (TACE-PAI group) and 103 patients who were not indicated for, or did not receive, TACE were treated with PAI therapy alone (PAI group). A portion of the study patients belonged to a previous clinical trial comparing the efficacy of PAI versus TACE-PAI therapy [31]. In the TACE-PAI group, TACE was performed up to a maximum of three courses, or discontinued when any of the following conditions developed: (i) feint or no tumor stain on hepatic angiography; (ii) feeding artery not accessible by catheter; (iii) deterioration of liver function as reflected by increase >1 mg/dl in serum total bilirubin level and decrease >0.5 g/dl in serum albumin. PAI therapy was then administered to the remaining viable part of tumor nodule as reflected by dynamic CT scan showing contrast enhancement in the arterial phase.
Post-treatment follow-up included ultrasound scan and measurement of serum AFP levels every 2 months, and contrast-enhanced dynamic CT every 34 months. MRI and/or hepatic angiography were carried out as supplemental examinations. Treatment response was evaluated after the completion of initial treatment cycle in both TACE-PAI and PAI groups. An additional treatment cycle was administered once tumor recurrence or viable tumor was found. When patients developed a diffuse, infiltrative HCC, they were considered non-responsive and not treated.
Assessment of treatment response
Complete treatment response (no neoplastic disease), according to WHO criteria [32], was defined as absence of contrast-enhanced area in CT scan and no tumor staining in angiography of the treated tumor. Detection of local residual disease was defined as a recurrent tumor within or adjacent to the treated tumor, and the occurrence of intrahepatic metastasis was defined as new tumor recurrence elsewhere, separate from the treated tumor. Patients were considered to have complete response only when all treated tumors in the same subject showed complete necrosis by contrast-enhanced CT and hepatic angiography. Residual or new intrahepatic tumor recurrence was detected by the CT showing contrast enhancement during arterial phase or angiography showing tumor staining. The primary and secondary end points of this study were patient treatment response and the development of intrahepatic metastasis, respectively.
Statistical methods and risk factor analysis
All statistical analyses were carried out using SPSS for Windows, release 11.0.1. The 2-test or Fishers exact test (two-tailed) was used for categorical data, and the MannWhitney ranked sum test was used for continuous data. The survival curve of the association of complete tumor necrosis after treatment and the development of intrahepatic metastasis was estimated by the KaplanMeier method, and compared by the log-rank test. The patient- and tumor-related variables including age, sex, underlying hepatitis, Child-Pugh class, number and size of tumors, CLIP score, serum levels of albumin, bilirubin and AFP, prothrombin time ratio, treatment modality, and treatment response were included for analysis. The occurrence of intrahepatic metastasis over time was treated as a time-dependent covariate, and its association with overall survival was examined using a Cox multivariate analysis. Factors that were significant or marginally significant (P <0.1) in the univariate survival analysis were entered into a Cox proportional hazard model to determine the adjusted risk ratios. For all tests, a P value <0.05 was considered statistically significant.
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Results |
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Discussion |
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The overall cumulative rate of intrahepatic metastasis at 3 years was 68% in this series. Such a high rate of recurrence is not unusual, because of the multicentric nature of the disease. It is noteworthy that the development of intrahepatic metastases in a substantial proportion of patients may be attributed to the multiple metachronous or unnoticed synchronous tumors that could not be detected even by the highly sensitive contemporary radiological imaging modalities used [35, 36]. Nevertheless, a high tumor recurrence rate is not a specific drawback of percutaneous or transarterial approach, because it is also found in cirrhotic patients with HCC treated with curative surgical resection [35, 36]. An important finding in this study is that the difference in the cumulative incidence of intrahepatic metastasis between those with and without initial complete response was most striking after 2 years of treatment (Figure 1), suggesting that complete tumor eradication could effectively suppress new carcinogenesis foci.
Various forms of locoregional therapy have been widely performed in treating unresectable HCCs, but complete cure of HCC cannot be expected. In many occasions, a small portion within the tumor nodule may still remain viable after repeated treatment such as TACE or percutaneous injection therapy. For patients with HCC, histological studies of resected HCC specimens after TACE procedure showed that complete necrosis occurred in only 2250% of HCC lesions [3740]. Similarly, for patients who underwent percutaneous injection therapy, the injected chemical might not be able to effectively destroy the intra-tumoral septum and penetrate the entire tumor nodule [16, 20, 21]. Therefore, the residual viable cancer cells may facilitate tumor progression and induce intrahepatic metastasis, as shown in a previous study which suggested that in most instances, intrahepatic recurrences are considered to arise from intrahepatic metastasis by means of venous dissemination or microsatellites [41].
In addition to initial treatment response, large tumor size (>3 cm) was also identified as a risk factor that may predispose to intrahepatic metastasis. This result is in agreement with previous findings in surgical and non-surgical series. Large-sized tumor nodules more often had concomitant minute cancerous lesions, and it has been shown that tumor recurrence was frequent in patients with large HCC even when the tumor has been removed by surgical resection or liver transplantation [36, 36]. Patients with large HCC undergoing TACE [79] or percutaneous ethanol injection therapy [1217] were also often associated with a relatively poor long-term outcome. However, the significance of tumor size was excluded in the adjusted Cox multivariate model, suggesting that treatment response was a stronger and prevailing factor influencing intrahepatic metastasis.
The occurrence of new tumor over time in the remnant liver may compromise further active treatment, partly because it has frequently been linked with concurrent liver decompensation at the time of diagnosis [42]. To determine the prognostic impact of intrahepatic metastasis, this factor was analyzed as a time-dependent covariate, and was consistently identified as an independent factor predicting a decreased survival, with an increased risk ratio of up to 3.2-fold.
In conclusion, our results indicate that successful induction of initial complete treatment response may have important therapeutic implications. It could both reduce the incidence of intrahepatic metastasis and prolong survival in HCC patients who undergo locoregional ablation therapy. Aggressive initial anticancer treatment directed at inducing effective locoregional control may be necessary to achieve a more favorable long-term outcome.
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Acknowledgements |
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FOOTNOTES |
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REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2. Hussain SA, Ferry DR, El-Gazzaz G et al. Hepatocellular carcinoma. Ann Oncol 2001; 12: 161172.[Abstract]
3. Kawasaki S, Makuuchi M, Miyagawa S et al. Results of hepatic resection for hepatocellular carcinoma. World J Surg 1995; 19: 3134.[ISI][Medline]
4. Nagasue N, Uchida M, Makino Y et al. Incidence and factors associated with intrahepatic recurrence following resection of hepatocellular carcinoma. Gastroenterology 1993; 105: 488494.[ISI][Medline]
5. Izumi R, Shimizu K, Li T et al. Prognostic factors of hepatocellular carcinoma in patients undergoing hepatic resection. Gastroenterology 1994; 106: 720727.[ISI][Medline]
6. Bismuth H, Majno PE, Adam R. Liver transplantation for hepatocellular carcinoma. Semin Liver Dis 1999; 19: 311322.[ISI][Medline]
7. Llovet JM, Real MI, Montana X et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 2002; 359: 17341739.[CrossRef][ISI][Medline]
8. Okuda K, Ohtsuki T, Obata H et al. Natural history of hepatocellular carcinoma and prognosis in relation to treatment: study of 850 patients. Cancer 1985; 56: 918928.[ISI][Medline]
9. Shijo H, Okazaki M, Higashihara H et al. Hepatocellular carcinoma: a multivariate analysis of prognostic features in patients treated with hepatic arterial embolization. Am J Gastroenterol 1992; 87: 11541159.[ISI][Medline]
10. Huang YH, Wu JC, Chau GY et al. Supportive treatment, resection and transcatheter arterial chemoembolization in resectable hepatocellular carcinoma: an analysis of survival in 419 patients. Eur J Gastroenterol Hepatol 1999; 11: 315321.[ISI][Medline]
11. Lo CM, Ngan H, Tso WK et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 2002; 35: 11641171.[CrossRef][ISI][Medline]
12. Livraghi T, Giorgio A, Marin G et al. Hepatocellular carcinoma and cirrhosis in 746 patients: long-term results of percutaneous ethanol injection. Radiology 1995; 197: 101108.[Abstract]
13. Orlando A, DAntoni A, Camma C et al. Treatment of small hepatocellular carcinoma with percutaneous ethanol injection: a validated prognostic model. Am J Gastroenterol 2000; 95: 29212927.[ISI][Medline]
14. Shiina S, Tagawa K, Niwa Y et al. Percutaneous ethanol injection therapy for hepatocellular carcinoma: results in 146 patients. Am J Roentgenol 1993; 160: 10231028.[Abstract]
15. Vilana R, Bruix J, Bru C et al. Tumor size determines the efficacy of percutaneous ethanol injection for the treatment of small hepatocellular carcinoma. Hepatology 1992; 16: 353357.[ISI][Medline]
16. Lencioni R, Bartolozzi C, Caramella D et al. Treatment of small hepatocellular carcinoma with percutaneous ethanol injection: analysis of prognostic factors in 105 Western patients. Cancer 1995; 76: 17371746.[ISI][Medline]
17. Kotoh K, Sakai H, Sakamoto S et al. The effect of percutaneous ethanol injection therapy on small solitary hepatocellular carcinoma is comparable to that of hepatectomy. Am J Gastroenterol 1994; 89: 194198.[ISI][Medline]
18. Huo TI, Huang YH, Wu JC et al. Survival benefit of cirrhotic patients with hepatocellular carcinoma treated by percutaneous ethanol injection as a salvage therapy. Scand J Gastroenterol 2002; 37: 350355.[CrossRef][ISI][Medline]
19. Ohnishi K, Yoshioka H, Ito S et al. Prospective randomized controlled trial comparing percutaneous acetic acid injection and percutaneous ethanol injection for small hepatocellular carcinoma. Hepatology 1998; 27: 6772.[ISI][Medline]
20. Ohnishi K, Nomura F, Ito S et al. Prognosis of small hepatocellular carcinoma (less than 3 cm) after percutaneous acetic acid injection: study of 91 cases. Hepatology 1996; 23: 9941002.[ISI][Medline]
21. Ohnishi K, Yoshioka H, Ito S et al. Treatment of nodular hepatocellular carcinoma larger than 3 cm with ultrasound-guided percutaneous acetic acid injection. Hepatology 1996; 24: 13791385.[ISI][Medline]
22. Huo TI, Huang YH, Wu JC et al. Comparison of percutaneous acetic acid injection and percutaneous ethanol injection for hepatocellular carcinoma in cirrhotic patients: a prospective controlled study. Scand J Gastroenterol 2003; 38: 770778.[ISI][Medline]
23. Livraghi T, Goldberg SN, Lazzaroni S et al. Small hepatocellular carcinoma: treatment with radio-frequency ablation versus ethanol injection. Radiology 1999; 210: 655661.
24. Yamamoto J, Okada S, Shimada K et al. Treatment strategy for small hepatocellular carcinoma: comparison of long-term results after percutaneous ethanol injection therapy and surgical resection. Hepatology 2001; 34: 707713.[CrossRef][ISI][Medline]
25. Simonetti RG, Liberati A, Angiolini C et al. Treatment of hepatocellular carcinoma: a systematic review of randomized controlled trials. Ann Oncol 1997; 8: 117136.[Abstract]
26. Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology 2003; 37: 429442.[CrossRef][ISI][Medline]
27. Bruix J, Sherman M, Llovet JM et al. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. J Hepatol 2001; 35: 421430.[CrossRef][ISI][Medline]
28. Pugh RNH, Murray-Lyon IM, Dawson JL et al. Transection of the esophagus for bleeding oesophageal varices. Br J Surg 1973; 60: 646649.[ISI][Medline]
29. Cancer of the Liver Italian Program (CLIP) Investigators. A new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients. Hepatology 1998; 28: 751755.[CrossRef][ISI][Medline]
30. Huang YS, Chiang JH, Wu JC et al. Risk of hepatic failure after transcatheter arterial chemoembolization for hepatocellular carcinoma: predictive value of the monoethylglycinexylidide test. Am J Gastroenterol 2002; 97: 12231227.[CrossRef][ISI][Medline]
31. Huo TI, Huang YH, Wu JC et al. Sequential transarterial chemoembolization and percutaneous acetic acid injection therapy versus repeated percutaneous acetic acid injection for unresectable hepatocellular carcinoma: a prospective study. Ann Oncol 2003; 14: 16481653.
32. Miller AB, Hoogstraten B, Staquet M et al. Reporting results of cancer treatment. Cancer 1981; 47: 207214.[ISI][Medline]
33. Castellano L, Calandra M, Del Vecchio Blanco C et al. Predictive factors of survival and intrahepatic recurrence of hepatocellular carcinoma in cirrhosis after percutaneous ethanol injection: analysis of 71 patients. J Hepatol 1997; 27: 862870.[CrossRef][ISI][Medline]
34. Pompili M, Rapaccini GL, Covino M et al. Prognostic factors for survival in patients with compensated cirrhosis and small hepatocellular carcinoma after percutaneous ethanol injection therapy. Cancer 2001; 92: 126135.[CrossRef][ISI][Medline]
35. Shuto T, Hirohashi K, Ikebe T et al. Additional hepatocellular carcinomas undetectable before surgery. World J Surg 2000; 24: 15661569.[CrossRef][ISI]
36. Huo TI, Wu JC, Lui WY et al. Reliability of the contemporary radiology to measure tumor size of hepatocellular carcinoma in patients undergoing resection: limitations and clinical implications. Scand J Gastroenterol 2004; 39: 4652.[CrossRef][ISI][Medline]
37. Nakamura H, Tanaka T, Hori S et al. Transcatheter embolization of hepatocellular carcinoma: assessment of efficacy in cases of resection following embolization. Radiology 1983; 147: 401405.[Abstract]
38. Sakurai M, Okamura J, Kuroda C. Transcatheter chemo-embolization effective for treating hepatocellular carcinoma: a histopathologic study. Cancer 1984; 54: 387392.[ISI][Medline]
39. Higuchi T, Kikuchi M, Okazaki M. Hepatocellular carcinoma after transcatheter hepatic arterial embolization: a histopathologic study of 84 resected cases. Cancer 1994; 73: 22592267.[ISI][Medline]
40. Takayasu K, Shima Y, Muramatsu Y et al. Hepatocellular carcinoma: treatment with intraarterial iodized oil with or without chemotherapeutic agents. Radiology 1987; 163: 345351.[Abstract]
41. Poon RT, Fan ST, Ng IO et al. Significance of resection margin in hepatectomy for hepatocellular carcinoma: a critical reappraisal. Ann Surg 2000; 231: 544551.[CrossRef][ISI][Medline]
42. Huo TI, Lui WY, Wu JC et al. Deterioration of hepatic functional reserve in patients with hepatocellular carcinoma after resection: incidence, risk factors and association with intrahepatic tumor recurrence. World J Surg 2004; In press.