T. U. Haq  ( Department of Radiology, Aga Khan University Hospital, Karachi. )

Hepatocellular Carcinoma (HCC) is extremely lethal and an overall median survival without treatment is 1.6 months.1 There are two main causes of death: deterioration due to tumour growth, and hepatic failure. Prognostic factors include size and number of lesions, vascular invasion, infiltrative behavior, capsular invasion and distant metastasis. The prognosis is closely related to liver function reserves. Ohnishi et al2 reported the natural history of HCC without treatment and demonstrated median survival times of 37 months for Child's A, 16 months for Child's B and 2 months for Child's C patients.
Okuda et al1 introduced a simple and practical staging system for HCC. Only four clinical signs are used for the staging (a) more than 50% tumour size (b) ascites (c) less than 3mg/dl of serum albumin and (d) more than 3 mg/dl of serum bilirubin.
Stage I - no above signs
Stage II - 1-2 clinical signs
Stage III - 3-4 clinical signs
The median survival of 229 patients with no specific treatment at Stages I, II and III were 8.3 months, 2.0 months and 0.7 months respectively.
Detection of Early HCC
Establishment of screening ultrasound (US) and serum AFP of high risk groups such as hepatitis B or C carriers and liver cirrhotic patients and recent advances in medical imaging technology permit the early detection of small HCCs. The sensitivities of various imaging modalities for HCC of <3 cms is reported as:3,4
Ultrasound 46 - 84%
Helical CT 54 - 84%
Angiography 81%
CT arterioportography 88%
Iodized Oil CT 93%
MRI 90%
Intra-operative US 96%
Japanese recommendation for screening cirrhotic patients is to perform alpha-fetoprotein every 2 months, US every 3 months and CT or MRI every 6 months.5

Hepatic resection offers the best chance at cure for patients with hepatocellular carcinoma, but only 10-30% of such patients are eligible for resection.6 In addition, the recurrence rate in the remnant liver after a hepatectomy is markedly high, ranging from 36% - 66%.
The second best option would be hepatic transplantation, which is reserved for selected patients with cirrhotic liver disease who have tumour (diameter, <5 cm) in the context of neoadjuvant protocols. The long term survival is higher than resection7,8 but treatment is restricted due to limited facilities, selection criteria and long wait for donor livers.
Unresectable HCCs pose a challenge to both oncologists and interventional radiologists. The results of systemic chemotherapy and radiotherapy have been disappointing with no appreciable impact on survival rates.9 Although the direct application of intra-arterial chemotherapy into the feeding artery of a tumour is theoretically much more effective and produces less toxicity than systemic intravenous chemotherapy, the benefit and safety of this treatment has not been proved in clinical trials.10,11
Hepatic artery embolization, in combination with chemotherapy was developed in Japan in early 80s for unresectable HCC.12 It is now fairly well established as primary treatment for non-resectable HCC.13 The rationale for transarterial chemo-embolization (TACE) is that these tumours especially the well-encapsulated lesions are mainly fed by the hepatic artery. By contrast the infiltrative tumours also have a supply from the portal vein. On the basis of many clinical studies14 it has been speculated that when iodized oil (Lipoidol Ultra-Fluid) is used to embolize HCC, the oil enters the sinusoids, where it is retained. Oil particles have been found in the portal vein following an arterial injection. The oil is mixed with the cytotoxic agent such as Cisplatinum, Doxorubicin, Epirubicin or Mitomycin C to form a covalent conjugate, which is then injected into the feeding artery. The conjugate remains in the tumour acting from both arterial and portal side and the cytotoxic agent is slowly released to exert the chemotherapeutic effect. Lipoidol serves as both the targeting agent that carries the cytotoxic agent to the tumour, since it is selectively deposited in it and the embolizing agent that causes blockade of neovasculature of the tumour. The daughter tumours are also dealt with in the segment or lobe which is injected.15
Gelfoam particles appear to be essential to maximize the therapeutic effect of TACE. They increase the retention of iodized oil by blocking washout. Takuyasu et al16 found that complete necrosis occurred in 83% with triple therapy (Lipoidol, adriamycin and gelfoam), but occurred in only 13% with oil and adriamycin.

Several reports from the 1990's consistently show a 2-3 fold increase in median survival after chemoembolization compared to untreated controls17,18 (Table). Survival varies directly with tumour encapsulation, oil uptake and retention, and inversely with tumour volume, infiltration and underlying liver disease. Post-operative recurrent HCCs have also been treated by TACE.19 Iodized oil can reach recurrent tumours even through the small collateral vessels that often develop after repeated TACE and previous surgery. Although unresectable tumours have become resectable after successful TACE20, pre-operative TACE for resectable HCCs is controversial.

Doxorubicin Hydrochloride (Adriamycin [ADR]) has been the main anticancer agent used in TACE. The standard dose is 20-30 mg/m2 (20-90 mg; mean 40 mg). The dose would be adjusted according to the size and number of tumours, embolized area and liver function.
Epirubicin (EPI), analog to Adriamycin, has less acute toxicity (nausea, vomiting), less myelosuppression on an equivalent milligram basis and higher total allowed cumulative dose before the onset of congestive heart failure.21 To attain equivalent biological effect of ADR, approximately 25% more EPI must be given, so that 25-40 mg/m2 is equivalent to 20-30 mg/m2 of ADR.
Cisplatinum (60 mg/m2) and Mitomycin C (0.2 mg/Kg) are effective alternatives. They can be used when a patient shows clinical evidence of ADR cardiotoxicity or when a synergestic effect is anticipated.

Overall complication rate of TACE is reported to be 4.4%22 and related to the use of chemoembolic agents or the manipulation of a catheter or guide wire. The most common complication is post embolization syndrome (nausea, vomiting, abdominal pain, loss of appetite and daily intermittent fevers - temperature below 39oC). This syndrome can occur with any solid organ embolization. With current medical care (hydration, antiemetics and pain control) the symptoms are well tolerated and 50% of patients can be discharged from the hospital the day following chemoembolization. Extent and duration of fever appears to be related to the degree of tumour necrosis and to tumour size. These symptoms improve with time.
Other complications are listed below23:
1. Puncture site hematoma 1.6%
2. Peripheral artery occlusion 0.4%
3. Catheter induced complications 0.4%
4. Contrast media reactions 4.0%
5. Renal failure 2.4%
6. Prolonged fever 0.4%
7. Liver abscess 0.4%
8. Mortality 2.0%
9. Liver infarction 0.17%
10. Acute hepatic failure 0.26%
11. Intrahepatic biloma formation 0.87%
12. Cholecystitis and gallbladder infarction 0.30%
13. Splenic infarction 0.08%
14. GI mucosal lesions 0.22%
15. Tumour rupture 0.04%
16. Variceal bleeding 0.13%

Colorectal Metastasis

Phase II studies of chemoembolization for metastasic colorectal cancers have been reported by several centers in US with promising results. At the Boston Center for liver cancer, 40 paients were chemoembolized26 with 5FU, Mitomycin C, oil and gelfoam. Sixty three percent had partial or minor morphological responses and 62% had a 50% drop in CEA level. Median survival from first chemoembolization was 10 months. At the University of Pennysylvania, 51 patients were chemoembolized.27 Morphological stabilization or regression occurred in 72%, CEA stabilized or regressed in 90% and the median duration of response was 12 months. The ACR Imaging Network is currently funding a multicenter Phase III randomized trial of systemic chemotherapy with or without chemoembolization for colorectal metastasis to liver.

Ocular Melanoma

Patients with ocular melanoma frequently develop rapidly progressive fatal hepatic metastasis, with median survival of 2-6 months. The M. D. Anderson Cancer Center reported on 30 patients treated by chemoembolization.28 There was one complete response and 46% of the patients had a >50% morphological response. Median survival was 11 months.

Neuroendocrine Tumours

Embolization has an established role in the palliation of these hypervascular tumours, typically producing symptom-free intervals of 5-10 months in 90-100% of patients.29 Other investigators have warned of an increased complication rate for chemoembolization of carcinoid tumours.

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