Case study 92.1
A 50-year-old patient with a history of hepatitis C was recently found to have multiple liver masses. Imaging showed several 3 cm lesions with classic hypervascularity in the arterial phase and washout in the venous phase compatible with hepatocellular carcinoma (HCC). Alpha-fetal protein was also elevated. The patient did not qualify for transplant due to the multiple numbers of lesions involving both lobes. The lesions were unable to be surgically resected and unable to be ablated.
• Outside of systemic therapy, what are the types of loco-regional therapy that are available?
If the lesions are inoperable and also unable to be ablated, a form of transarterial therapy can be considered. This procedure utilizes transarterial technique for chemoinfusion, bland embolization, chemoembolization, and radioembolization.
Transarterial chemoinfusion (aka hepatic artery infusion (HAI)) utilizes the drug’s first-pass extraction rate pharmacokinetic principle. For example, floxuridine has a hepatic extraction rate of 95%, which significantly reduces the systemic toxicity. Recently, Okusaka et al. (2009) demonstrated that for inoperable HCC, HAI was as effective as transarterial chemoembolization. This randomized phase III prospective study with 161 patients showed there was no statistical difference of median overall survival time between chemoembolization group (646 days) versus HAI group (679 days) (P = 0.383). They concluded that by adding embolization, it did not increase survival over HAI in patients with HCC.
To discuss any form of transarterial embolization to the liver, one must understand the liver perfusion physiology. The liver has dual blood supply from the systemic arterial and portal inflows. Since more than two-thirds of the hepatic inflow is from the portal system, the liver can sustain itself from the portal flow alone. Embolization of the hepatic artery or of its branches will not cause liver infarction. However, tumor angioneogenesis, requiring higher oxygen content, is derived almost exclusively from the hepatic artery. This allows the introduction of antineoplastic agents directly into the tumor with significant less effect on the normal liver parenchyma.
Bland transarterial embolization employs use of various embolic materials to occlude the tumor-feeding arterioles. The primary goal is to induce ischemia and tumor necrosis without concomitant use of chemotherapy. Common embolic agents include gelfoam, polyvinyl alcohol, and calibrated acrylic copolymer microspheres. In general, the goal of embolization is to administer the agents deep into the tumor vascularity to cause cessation of flow and infarction. To obtain adequate tumor coverage, the adjacent surrounding normal liver parenchyma may be embolized as well. Embolic agents that are too small may cause severe complications. Hepatic embolization performed with gelatin powder has causes small vessel liver damage leading to biliary strictures. Even distal systemic complications, including fatal pulmonary complications, have been described.
In 2008, Maluccio et al. published their findings in 322 patients with inoperable HCC who underwent 766 transarterial embolizations utilizing small (50 μm) polyvinyl alcohol or spherical embolic particles (40–120 μm). The median survival time was 21 months, with 1-, 2-, and 3-year overall survival rates of 66%, 46%, and 33%, respectively. Okuda stage, extrahepatic disease, diffuse disease (≥5 tumors), and tumor size were independent predictors of survival on multivariate analysis.
Chemoembolization is defined as the infusion of a mixture of chemotherapeutic agents with or without ethiodized oil followed by embolization with particles as described in this chapter. By occluding the tumor vessels after administration of chemotherapeutic agents, the goal is to obtain arterial stasis of the chemotherapeutic agent at the tumor site and also to induce concomitant ischemia. It has been reported that the tissue concentrations of the chemotherapeutic agents within tumors is as high as 40 times that of the surrounding normal liver parenchyma. Due to variations in transarterial techniques, in embolic materials, and in the combinations of chemotherapeutic agents and its doses (primarily doxorubicin, cisplatin, and mitomycin), no standardized protocol has been adopted. Marelli et al. (2007) reviewed 175 cohorts and randomized trials testing transarterial therapies and reached the conclusion that no chemotherapeutic agent appeared better than any other. Despite this, chemoembolization has been demonstrated to be effective with inoperable HCC. In 2002, Llovet et al. (2002) and Lo et al. (2002), both demonstrated, in their prospective randomized controlled trials, that chemoembolization improved survival of stringently selected patients with unresectable HCC over conservative treatment. Llovet et al. demonstrated that in 40 patients with Child–Pugh class A or B and Okuda stage I or II, survival probabilities at 1 year and 2 years were, respectively, 75% and 50% for embolization, 82% and 63% for chemoembolization, and 63% and 27% for control (chemoembolisation vs. control, P = 0.009). Lo et al. also reported findings of a select group of patients with unresectable HCC treated with chemoembolization that resulted in a marked tumor response, and the actuarial survival was significantly better in the chemoembolization group (1 year, 57%; 2 years, 31%; 3 years, 26%) than in the control group (1 year, 32%; 2 years, 11%; 3 years, 3%; P = .002).
A more controlled and sustained method of releasing chemotherapy is thought to be obtained with chemoembolization using drug-eluting beads. These beads, made of sulfonate-modified poly (vinyl alcohol) hydrogel or copolymer microsphere and loaded with chemotherapy (e.g., doxorubicin and irinotecan), are used for chemoembolization. Significant reductions of peak plasma concentrations have been described. Malagari et al. (2010) reported a randomized prospective study using drug-eluting bead (DEB) chemoembolization and bland chemoembolization of intermediate-stage HCC (HCC). At 6 months, a complete response was seen in 11 patients (26.8%) in the DEB-chemoembolization group and in 6 patients (14%) in the bland embolization group; a partial response was achieved in 19 patients (46.3%) and 18 (41.9%) patients in the DEB-chemoembolization and bland embolization groups, respectively. Recurrences at 9 and 12 months were higher for bland embolization (78.3% vs. 45.7%) at 12 months. Time to progression (TTP) was longer for the DEB-chemoembolization group (42.4 ± 9.5 and 36.2 ± 9.0 weeks), at a statistically significant level (P = 0.008).
The final embolic material to be discussed is radioembolization. Glass or resin microspheres embedded with radioactive isotope 90Y are directly infused into the hepatic arteries feeding the tumor. The microspheres are smaller than other embolic material ranging from 20 to 60 μm, allowing them to embed within the aberrant peripheral vascular plexus of the tumor tissue. Yttrium-90 is a pure beta-emitter with a half-life of 64.2 hours. The tissue penetration range of the emissions is 2.5 to 11 mm. The treatment is also categorized as brachytherapy requiring dosimetry planning, administration and delivery of radioactive material and adjustment of dose depending on tumor and hepatic volume as well as pulmonary shunting. The radiation dose administered can be high as 150 Gy. TheraSphere (glass) is approved by the US Food and Drug Administration under humanitarian device exemption for the treatment of unresectable HCC. SIR-Sphere (resin) has full premarketing approval for the treatment of colorectal metastases in conjunction with intrahepatic FUDR. Both are being used for treatment of multiple types of liver cancers either via oversight by the local Institutional Review Board or via off-label endovascular catheter-based infusion. Carr (2004) has reported, in 65 patients with unresectable HCC treated with Y90, that a median survival for Okuda stage I patients (n = 42) was 649 days (historical comparison: 244 days) and for Okuda stage II patients (n = 23) was 302 days (historical comparison: 64 days).
• So, which transarterial treatment options will be best for this patient?
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