Chemoembolization and Radioembolization for the Treatment of Liver Metastases

PICHON RIVIERE, A.; AUGUSTOVSKI, F. A.; GARCIA MARTI, S.; GLUJOVSKY, D.; ALCARAZ, A.; LOPEZ, A.; BARDACH, A.; CIAPPONI, A

Documento de Evaluación de Tecnologías Sanitarias

IECS

Año: 2012 p. 1 - 30

1668-2793

The liver is one of the most common locations for distant metastases. The most common origin of these metastases is colorectal cancer which is among the three most common cancers, both in women and in men.In general, surgical resection is the first therapeutic option although most patients are not eligible for this kind of intervention. Other treatment options include systemic chemotherapy, radiotherapy, thermal ablation and radiofrequency ablation. Survival in patients with unresectable liver metastases is estimated in less than 10 months if only palliative care were used. However, chemotherapy administration has significantly prolonged survival.Since both chemotherapy and conventional radiotherapy are associated to adverse effects, other alternatives such as chemoembolization and radioembolization have emerged as therapeutic alternatives. Furthermore, the use of these alternatives is proposed mainly as salvage therapy when systemic therapies have not been efficacious or else, as primary indication in cases where a non-surgical patient needs to be converted into a surgical one.TechnologyChemoembolization with slow-release microspheres is a type of intra-arterial chemotherapy in which microspheres are released into the liver arteries through conventional catheters or microcatheters allowing transportation of chemotherapy drugs such as irinotecan. The occlusion of the arterial net results in ischemia and further necrosis of the tumor cells in addition to releasing large amounts of drug for prolonged periods of time. For radioembolization, radioactive microspheres that would act in a similar way, but which contain beta-radiating yttrium-90 isotope are injected.PurposeTo assess the available evidence on the efficacy, safety and coverage policy related aspects on the use of chemoembolization and radioembolization in patients with liver metastases.MethodsA bibliographic search was carried out on the main databases: DARE, NHS EED, on Internet general search engines, in health technology evaluation agencies and health sponsors. Priority was given to the inclusion of systematic reviews; controlled, randomized clinical trials (RCTs); health technology assessments and economic evaluations; clinical practice guidelines and coverage policies of other health systems.ResultsTwo SRs (Systematic Reviews), two RCTs (Randomized Clinical Trials) on chemoembolization and three RCTs on radioembolization, two clinical practice guidelines, four documents on health technology assessments and health policies of several sponsors have been evaluated.A systematic review about chemoembolization in patients with liver metastases was published in 2012. Only one RCT published in 1990 was found. No significant differences were found in mortality in both studied arms.In 2010, one RCT on 44 patients with refractory unresectable metastases who received fluorouracil (FU) versus radioembolization plus FU was published. Time to liver progression was 2.1 and 5.5 months respectively (HR=0.38; 95%CI 0.20 to 0.72; p<0.01). There were no significant differences regarding toxicity or overall survival, with a 24-month median follow-up.In 2012, a RCT on 74 patients with unresectable liver metastases from colorectal carcinoma which occupied less than 50% of the liver was published. One arm received chemoembolization with irinotecan, whereas the other received systemic therapy with irinotecan, 5-FU and leucovorin. At 50 months, survival was higher in the chemoembolization group with median survivals of 22 and 15 months, respectively (p=0.03), as well as disease free survival of 7 versus 4 months (p<0.01). Differences in quality of life improvement were also observed (8 vs. 3 months, p<0.01).In 2001 and 2004, two RCTs which included 74 and 21 patients with untreated colorectal liver metastases were published. The patients were randomized to radioembolization plus chemotherapy or chemotherapy alone. The response rate as well as time to disease progression was significantly higher in the group using radioembolization.In 2012, another systematic review about chemo and radioembolization in patients with unresectable liver metastases of neuroendocrine tumors was published. Thirty seven case series showing similar survival results for both technologies were found.In addition, in 2012 one RCT including 26 patients with unresectable liver metastases of neuroendocrine origin who received liver artery embolization or liver artery chemoembolization was published. There were no statistically significant differences in terms of survival.The HTAs reviewed do not agree. Both a report from Canada (CADTH) and from the United Kingdom (NICE) concluded that radioembolization seems to be a safe and efficacious therapy for patients with unresectable liver tumors, and that results may improve when combined with systemic chemotherapy, and they propose it as last treatment line for patients with liver tumors refractory to other treatments. On the contrary, the Australian Ministry of Health excludes radioembolization coverage for any type of metastasis, in line with Argentina´s Health Service Superintendence, which considers there is still not enough evidence to make a general recommendation.Most U.S. health sponsors assessed provide radio and chemoembolization coverage for the treatment of unresectable liver metastases (although some differ based on the origin of metastases, coverage being more consistent for neuroendocrine tumors).ConclusionsThe evidence on the use of chemo and radioembolization for patients with liver metastases is still limited. Although some studies have demonstrated the benefits of these therapies, mainly in studies which added radioembolization to chemotherapy, others did not demonstrate significant differences. There is still no clear evidence if one therapeutic alternative is more beneficial than the other.Its use has been proposed mainly as last line treatment when there are unresectable, refractory metastases only located in the liver. The conclusions obtained from the different HTAs are contradictory and its coverage is mainly accepted, specially for metastases of neuroendocrine origin.More studies are needed to determine if its use may be beneficial in a specific clinical setting.