The Society of Interventional Radiology has published a position statement regarding arterial chemoembolisation of hepatic malignancies. The document, which highlights numerous clinical case studies and trials, concludes "hepatic arterial chemoembolisation is a safe, proven, and effective technique for the treatment of a number of malignancies, including hepatocellular carcinoma (HCC), neuroendocrine tumours, cholangiocarcinoma and ocular melanoma and sarcoma." The position statement is featured in the Journal of Vascular and Interventional Radiology (2006; 17:217-223) and was authored by Drs Daniel B Brown, Jean-Francois H Geschwind, Michael C Soulen, Steven F Millward and David Sacks.
The authors claim primary and secondary malignancies in the liver present one of the "most challenging problems in clinical oncology", with HCC one of the most common fatal malignancies worldwide, with more than 530,000 new cases diagnosed annually. They estimate that currently some 10,000-15,000 cases of HCC are diagnosed annually in the US and it was estimated that this number will more than double to 34,000 cases of HCC per year by 2019 (the prevalence of hepatoma in the United States in particular is rapidly increasing as a result of the spread of chronic infection with hepatitis C).
In addition, they cite colorectal cancer as the second leading cause of cancer-related death in the United States, with liver metastases accounting for approximately half these deaths. More than 56,000 patients died from colon cancer in 2002 and it is predicted that there will be more than 145,000 new cases of colorectal cancer diagnosed in the United States in 2005. Other tumours that frequently develop fatal hepatic metastases despite a treatable primary tumour include ocular melanoma, neuroendocrine tumours and gastrointestinal sarcoma.
Alternative therapies
The authors note that although surgical resection remains the gold standard for HCC, fewer than 20% of patients with HCC are candidates for surgery and even in a highly pre-selected group, postoperative mortality is a significant potential risk, with incidences ranging from 1.3% to 7%. The potential benefits of surgery are prolonged survival and maintenance of a disease-free state, with patients who undergo curative surgery having a 34%-59% five-year survival rate, and at five years, 13%-40% are disease free. However, the majority of patients are not surgical candidates and other options are considered such as transplantation (those patients with a limited tumour burden), chemotherapy (which the authors note is largely ineffective) and does not appreciably affect survival.
Chemoembolisation
Chemoembolisation combines hepatic artery embolisation with simultaneous infusion of a concentrated dose of chemotherapeutic drugs followed by embolisation particles. Hepatic artery embolisation refers to infusion of particles into tumour-feeding arteries without chemotherapeutic agents. Embolisation by either technique renders the tumour ischaemic. When chemotherapy is used, tumour drug concentrations are one to two orders of magnitude greater than are achieved by infusion alone and the dwell time of the chemotherapy agent is markedly prolonged, with measurable drug levels present as long as one month later. Because most of the drug is retained in the liver, systemic toxicity is reduced.
According to the authors, an advantage of embolisation is that the ischaemia induced by embolisation helps to overcome drug resistance by causing metabolically active cell membrane pumps to fail, thereby increasing intracellular retention of the chemotherapeutic drugs. The authors state that recent research has demonstrated that ischaemia can increase angiogenesis in tumour cells, possibly spurring tumour growth. These molecular changes raise questions about whether chemoembolisation or hepatic arterial embolisation is the better method to perform endovascular hepatic arterial therapy. To date, no study has demonstrated a difference in survival between the two techniques. However, only chemoembolisation has demonstrated a survival benefit in prospective randomised trials.
The position statement then moves on to provide clinical evidence that chemoembolisation is accepted worldwide as an effective treatment for patients with unresectable HCC and adequate preservation of liver function. The authors state that research has shown, even in patients who are potential candidates for resection, chemoembolisation results in similar projected five-year survival rates compared with surgery (26% for chemoembolisation vs 42% for surgery; p=.556)(1).
Furthermore, among 38 patients who underwent chemoembolisation in the study of Solomon et al(2), 62% of whom had Okuda stage 2 disease, median time to progression was greater than 1 year and survival rates were 60%, 41%, and 16% at 1, 2, and 3 years. The authors cite another study of 81 patients by Brown et al(3), which demonstrated 61%, 42%, and 32% survival rates at 1, 2, and 3 years after chemoembolisation. In direct contrast, the authors note survival rates among a contemporary series of 618 European and North American patients with hepatoma who were not treated with chemoembolisation were 31%, 19%, and 13% at 1, 2, and 3 years(4).
Results of randomised trials and HCC
The authors document that despite the large volume of single-institution experiences with chemoembolisation of hepatoma published during the past two decades, few randomised controlled trials have been reported. The reason given include trials that are fraught with structural flaws (during the evolution of the procedure) that limit the value of information obtained from each and because none of the early trials reflect the treatment of hepatoma as practiced in the United States. In particular, treatment of patients with only minimal disease and normal hepatic function does not represent the presentation of the majority of patients with HCC in the United States, and therefore generalised conclusions cannot be drawn from the results.
However, the authors cite two recent prospective randomised trials that both demonstrated significantly longer survival with chemoembolisation. The first, by Lo et al(5), compared survival outcomes with chemoembolisation versus symptomatic management, with 40 patients per group. One, 2-, and 3-year survival rates in the study group were 57%, 31%, and 26% respectively, compared with 32%, 11%, and 3% in the control group (P = .02). On univariate analysis, chemoembolisation remained a significant predictor of survival (odds ratio, 0.49; P =.006). The second study, by Llovet et al(6), included 112 patients in three arms and compared outcomes with chemoembolisation versus embolisation alone versus symptomatic treatment. The trial was stopped when a significant survival benefit was demonstrated with chemoembolisation (survival rates, 82% at 1 year and 63% at 2 years) versus symptomatic treatment (63% at 1 year and 27% at 2 years; P = .009). At the time the trial was halted, the authors note, there was not a survival benefit identified with embolisation alone (75% at 1 year and 50% at 2 years) versus symptomatic treatment, although the difference may have reached significance with continuation of the trial. The only variable associated with prolonged survival was assignment to the chemoembolisation group (odds ratio, 0.45; P = .02).
The authors claim that the dearth of randomised controlled trials for HCC in the United States reflects the reality that patients seeking treatment at cancer centres are not willing to be randomised to receive no therapy, especially as chemoembolisation is a widely accessible treatment with a 20-year track record for this disease. Additionally, survival in well-constructed trials from Asia and Europe during the past few years has demonstrated a significant benefit to treatment. For these reasons, it is highly unlikely that there will ever be a prospective randomised controlled trial of chemoembolisation for HCC in the United States. They claim that decisions regarding the merits of this therapy must be made based on the best available data. Moreover, the authors note that approval for treatment by third-party payers should not be withheld based on the absence of randomised controlled trial data that will never be produced.
Conclusion
The authors claim that embolisation of the liver has been performed for decades for a variety of indications and is well-tolerated. Embolisation of solid organs causes a self limited postembolisation syndrome in the majority of patients, consisting of varying degrees of pain, nausea, vomiting, and fever. This is independent of chemotherapeutic drug use, reason for embolisation (eg, bleeding, tumour), and the organ treated (eg, liver, kidney, spleen and uterus). With current medical care (eg, hydration, antiemetic therapy, and pain control), postembolisation syndrome is well-tolerated, and 50% of patients can be discharged from the hospital the day after chemoembolisation.
In conclusion, the authors state that arterial chemoembolisation, "has a palliative role for patients with colon carcinoma [and] may be useful with patients who have hepaticdominant metastatic disease from other primary malignancies. The benefit of chemoembolisation for these individuals should be evaluated on a case-by-case basis."
The position statement is available to read online at:
http://www.sirweb.org/clinical/cpg/217.pdf
References
(1) Lee HS, Kim KM, Yoon JH, et al. Therapeutic efficacy of transcatheter arterial chemoembolisation as compared with hepatic resection in hepatocellular carcinoma patients with compensated liver function in a hepatitis B virus-endemic area: a prospective cohort study. J Clin Oncol 2002; 20:4459- 4465.
(2) Solomon B, Soulen MC, Baum RA, et al. Chemoembolisation of hepatocellular carcinoma with cisplatin, doxorubicin, mitomycin-C, Ethiodol, and polyvinyl alcohol: prospective evaluation of response and survival in a U.S. population. J Vasc Interv Radiol 1999; 10:793-798.
(3) Brown DB, Fundakowski CE, Lisker- Melman M. Comparison of MELD and Child-Pugh scores to predict survival after chemoembolisation for hepatocellular carcinoma. J Vasc Interv Radiol 2004; 15:1209-1218.
(4) Chevret S, Trinchet JC, Mathieu D, et al. A new prognostic classification forpredicting survival in patients with hepatocellular carcinoma. Groupe d'Etude et de Traitement du Carcinome Hepatocellulaire. J Hepatol 1999; 31:133-141.
(5) Lo CM, Ngan H, Tso WK, et al. Randomized controlled trial of transarterial lipiodol chemoembolisation for unresectable hepatocellular carcinoma. Hepatology 2002; 35:1164-1171.
(6) 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; 359:1734-1739.
