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Aetna Aetna
Clinical Policy Bulletin:
Liver and Other Neoplasms - Treatment Approaches
Number: 0268
(Replaces CPB 338)

Policy

  1. Percutaneous Ethanol Injection

    Aetna considers percutaneous ethanol injection (PEI) medically necessary for the treatment of hepatocellular cancers (HCC) without extra-hepatic spread.

    Aetna considers PEI for liver neoplasms experimental and investigational when criteria are not met.  There is inadequate information to document the effectiveness of PEI as an alternative to surgical resection for the treatment of hepatic metastases. 

    Aetna considers combined radiofrequency ablation and PEI experimental and investigational for the treatment of HCC because of insufficient evidence in the peer-reviewed literature.

  2. Chemoembolization

    Aetna considers chemoembolization (CE) medically necessary for any of the following:

    1. For treatment of neuroendocrine cancers (i.e., carcinoid tumors and pancreatic endocrine tumors) involving the liver. For carcinoid tumors, CE is considered medically necessary only in persons who have failed systemic therapy with octreotide to control carcinoid syndrome (e.g., debilitating flushing, wheezing and diarrhea); or
    2. For unresectable, primary HCC; or
    3. For liver-only metastasis from uveal (ocular) melanoma; or
    4. Pre-operative hepatic artery chemoembolization followed by orthotopic liver transplantation for HCC.

    Aetna considers CE experimental and investigational for other indications including palliative treatment of liver metastases from other non-neuroendocrine primaries (e.g., breast cancer, cervical cancer, colon cancer, melanoma, rhabdomyosarcoma, or unknown primaries) and chemoembolization of the pancreas for pancreatic cancer because there is inadequate evidence in the medical literature of the effectiveness of CE for these indications.

  3. Intra-Hepatic Chemotherapy

    Aetna considers intra-hepatic chemotherapy (infusion) medically necessary for members with liver metastases from colorectal cancer.

    Aetna considers intra-hepatic chemotherapy experimental and investigational for other indications, including treatment of liver primaries or metastases from other primaries besides colorectal cancer because of insufficient evidence in the peer-reviewed literature.

    Aetna considers “one-shot” arterial chemotherapy for members with liver metastases from colorectal cancer experimental and investigational because of insufficient evidence in the peer-reviewed literature.

    Aetna considers transarterially administered gene therapy experimental and investigational for primary and secondary liver malignancies because of insufficient evidence in the peer-reviewed literature.

  4. Intra-Hepatic Microspheres

    Aetna considers intra-hepatic microspheres (e.g., TheraSphere, MDS Nordion Inc.; SIR-Spheres, Sirtex Medical Inc.) medically necessary for any of the following:

    1. For treatment of neuroendocrine cancers (i.e., carcinoid tumors and pancreatic endocrine tumors) involving the liver. For carcinoid tumors, intra-hepatic microspheres are considered medically necessary only in persons who have failed systemic therapy with octreotide to control carcinoid syndrome (e.g., debilitating flushing, wheezing and diarrhea); or
    2. For unresectable, primary HCC; or
    3. For unresectable liver tumors from primary colorectal cancer; or
    4. Pre-operative use as a bridge to orthotopic liver transplantation for HCC.

    Aetna considers intra-hepatic microspheres experimental and investigational for metastases from esophageal cancer and gallbladder cancer and other indications because of insufficient evidence in the peer-reviewed literature.

  5. Drug-Eluting Beads Trans-Arterial Chemoembolization

    Aetna considers drug-eluting beads trans-arterial chemoembolization experimental and investigational for leiomyosarcoma, and for primary and liver-dominant metastatic disease of the liver because of insufficient evidence in the peer-reviewed literature.

See also  CPB 0274 - Ablation of Hepatic Lesions.



Background

Chemoembolization (CE) involves the periodic injection of chemotherapy mixed with embolic material into selected branches of the hepatic arteries feeding liver tumors.  Chemoembolization has been successfully used as a palliative treatment of symptoms associated with functioning neuroendocrine tumors involving the liver.  The most common such tumor is the carcinoid tumor whose hormone production is associated with the carcinoid syndrome, characterized by debilitating flushing, wheezing and diarrhea.  Pancreatic endocrine tumors that produce gastrin, insulin or other pancreatic hormones are unusual types of neuroendocrine tumors.  Pancreatic endocrine (i.e., islet cell) tumors must be distinguished from the more common pancreatic epithelial tumors that arise from the exocrine portion of the pancreas.

The prognosis for patients with unresectable hepatocellular carcinoma (HCC) tumors is extremely poor.  Even in the case of small nodular lesions detected by US screening, patients receiving no treatment showed a mean 3-year survival rate of 12 %.  Among non-surgical options, percutaneous ethanol injection (PEI) can be considered the treatment of choice for patients with small HCC tumors.  Transcatheter arterial chemoembolization (TACE), most frequently performed by intra-arterially injecting an infusion of antineoplastic agents mixed with iodized oil (Lipiodol), has been extensively used in the treatment of large HCC tumors.  However, although massive tumor necrosis can be demonstrated in most cases, a complete necrosis of the tumor has rarely been achieved with TACE, since residual tumor can be found in a non-negligible number of the treated lesions.

Transcatheter arterial chemoembolization was found mostly effective in nodules less than 4 cm in diameter, with a thick tumor capsule.  In fact, small, encapsulated HCC are almost completely fed by hepatic arterial blood and therefore highly responsive to hepatic arterial embolization.  On the contrary, in unencapsulated tumors or in tumors showing extracapsular invasion of neoplastic cells, TACE often fails to induce complete necrosis since tumor cells, either unimpeded by the absence of a capsule or spreading across the capsule itself, invade the adjacent liver parenchyma, thus obtaining additional blood supply from the sinusoidal portal system.

Large HCC lesions can be more effectively treated with combined TACE and PEI.  In fact, alcohol diffusion is easier after the occurrence of the necrotic changes produced by TACE, thus allowing the intra-nodular injection of larger amounts of ethanol.  Moreover, after arterial embolization, the normal wash-out of the injected ethanol is more difficult in the tumorous area, resulting in longer retention of the substance.  The combination of TACE and PEI seems to be a highly effective treatment for large HCC also in the instances when daughter nodules are associated with a main tumor.  The presence of the capsule significantly enhances the chances of success and should be considered an important requirement when selecting patients to be submitted to TACE and PEI.

According to available literature, TACE may be indicated for symptomatic treatment of functional neuroendocrine cancers (i.e., carcinoid tumors and pancreatic endocrine tumors) involving the liver, in persons with adequate hepatic function (bilirubin less than 2 mg/dL, absence of ascites; no portal vein occlusion; and tumor involvement of less than 65 % of liver).  For carcinoid tumors, TACE is indicated only in persons who have failed systemic therapy with octreotide to control carcinoid syndrome (e.g., debilitating flushing, wheezing and diarrhea).  The safety and effectiveness of more than 4 TACE procedures is unknown. 

For unresectable, primary HCC, TACE is indicated in persons with small encapsulated nodules (less than 4 cm in diameter), no evidence of extra-hepatic metastases, and with adequate hepatic (serum bilirubin concentration less than 2.9 mg/dL) and renal function (serum creatinine less than 2.0 mg/dL). 

Pleguezuelo and colleagues (2008) stated that TACE improves survival in cirrhotic patients with HCC.  The optimal schedule, best anti-cancer agent and best technique are still unclear.  Transcatheter arterial chemoembolization may not be better than transarterial embolization (TAE).  Hepatocellular carcinoma is very chemoresistant, thus embolization may be more important than chemotherapy.  Lipiodol can not be considered as an embolic agent and there are no data to show that it can release chemotherapeutic agents slowly.  It can mask residual vascularity on CT imaging and its use is not recommended.  Both TACE and TAE result in hypoxia, which stimulates angiogenesis, promoting tumor growth; thus combination of TACE with anti-angiogenic agents may improve current results.  To date, there is no evidence that TACE pre-liver transplantation or resection helps to expand current selection criteria for patients with HCC, nor results in less recurrence after surgery.  Combination with other techniques, such as radiofrequency ablation (RFA) and drugs, may enhance the effect of TACE.  New trials are being conducted to clarify these issues.

Biolato et al (2010) provided an overview on the loco-regional therapy performed by TACE in patients with HCC, either as sole, either as neoadjuvant to surgery or bridge therapy to orthotopic liver transplantation (OLT).  Chemoembolization combines de-arterialization of the tumor and selective delivery of chemotherapeutic agents into tumor's feeding vessels during angiography.  Tumor ischemia raises the drug concentration compared to infusion alone and extends the retention of the chemotherapeutic drug. As loco-regional therapy, TACE allows a complete local tumor control of 25 to 35 % and permits an increase of survival in patients with intermediate HCC according to Barcelona-Clinic Liver Cancer (BCLC) classification.  Excellent results were also achieved by combined therapies, such as with PEI or RFA, as neoadjuvant therapy prior to liver resection and in some circumstances as a bridging tool before liver transplantation.  Drug eluting beads are microspheres that can be loaded with doxorubicin and induce toxic and ischemic necrosis with the same device; that allows an increase of drug selectively exposed to tumor cells and simultaneously a reduction of systemic toxicity.  Tumor embolization induces a neoangiogenic reaction with a significant growth of adjacent satellites, so the association with sorafenib has a strong rationale for a combined therapy and is currently under investigation.  The authors concluded that TACE is the standard of care for treatment of intermediate HCC.

Percutaneous ethanol injection has been shown to be effective only in primary HCC with a limited number (fewer than 4) of small foci (less than 5 cm in diameter) and with no evidence of extra-hepatic metastasis.  According to the medical literature, PEI is not suitable for persons with coagulopathy or ascites.  The National Comprehensive Cancer Network practice guidelines (NCCN, 2010) on hepatobiliary cancers stated that the 2 most commonly used methods of ablation therapy are PEI and RFA. 

In a randomized controlled study, Brunello and colleagues (2008) compared PEI and RFA for the treatment of early HCC.  A total of 139 cirrhotic patients in Child-Pugh classes A/B with 1 to 3 nodes of HCC (diameter 15 to 30 mm), for a total of 177 lesions were included in this study.  Patients were randomized to receive RFA (n = 70) or PEI (n = 69).  The primary end-point was complete response (CR) 1 year after the percutaneous ablation of all HCC nodes identified at baseline.  Secondary end-points were: early (30 to 50 days) CR, complications, survival and costs.  In an intention-to-treat analysis, 1-year CR was achieved in 46/70 (65.7 %) and in 25/69 (36.2 %) patients treated by RFA and PEI, respectively (p = 0.0005).  For lesions greater than 20 mm in diameter, there was a larger CR rate in the RFA-treated subjects (68.1 % versus 26.3 %).  An early CR was obtained in 67/70 (95.7 %) patients treated by RFA compared with 42/64 (65.6 %) patients treated by PEI (p = 0.0001).  Complications occurred in 10 and 12 patients treated by RFA and PEI, respectively.  The overall survival (OS) rate was not significantly different in the RFA versus PEI arm (adjusted hazard ratio = 0.88, 95 % confidence interval [CI]: 0.50 to 1.53).  There was an incremental health-care cost of 8,286 Euro for each additional patient successfully treated by RFA.  The authors concluded that the 1-year CR rate after percutaneous treatment of early HCC was significantly better with RFA than with PEI, but did not provide a clear survival advantage in cirrhotic patients.

Wong et al (2008) examined if combining PEI with RFA in the management of HCC in high-risk locations improves treatment outcomes.  These researchers compared the outcome of management of high-risk tumors with PEI and RFA (n = 50) or RFA alone (n = 114) with the outcome of RFA of non-high-risk tumors (n = 44).  They also compared the survival rates of patients with and those without high-risk HCC.  Percutaneous ethanol injection was performed into the part of the tumor closest to a blood vessel or vital structure before RFA.  The study included 142 patients with 208 HCCs managed with RFA.  Despite larger tumor sizes (2.8 +/- 1 cm versus 1.9 +/- 0.7 cm versus 2.5 +/- 0.1 cm for the high-risk RFA plus PEI, non-high-risk RFA, and high-risk RFA groups, respectively; p < 0.001), the primary effectiveness rate of high-risk RFA and PEI (92 %) was similar to that of non-high-risk RFA (96 %).  The primary effectiveness rate of high-risk RFA and PEI was slightly higher (p = 0.1) than that of high-risk RFA (85 %).  The local tumor progression rates (21 % versus 33 % versus 24 % at 18 months) of the 3 respective groups were not statistically different (p = 0.91).  Patients with and those without high-risk tumors had equal survival rates (p = 0.42) after 12 (87 % versus 100 %) and 24 (77 % versus 80 %) months of follow-up.  Independent predictors of primary effectiveness were a tumor size of 3 cm or less (p = 0.01) and distinct tumor borders (p = 0.009).  Indistinct borders (p = 0.033) and non-treatment-naive status of HCC (p = 0.002) were associated with higher local tumor progression rates.  The only predictor of survival was complete ablation of all index tumors (p = 0.001).  The authors concluded that the combination of RFA and PEI in the management of HCC in high-risk locations has a slightly higher primary effectiveness rate than does RFA alone.  They stated that a randomized controlled study is warranted.

In a Cochrane review, Schoppmeyer (2009) evaluated the beneficial and harmful effects of PEI or percutaneous acetic acid injection (PAI) in adults with early HCC.  A systematic search was performed in the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE, EMBASE, and ISI Web of Science in May 2009.  Meeting abstracts of 6 oncological and hepatological societies (ASCO, ESMO, ECCO, AASLD, EASL, APASL) and references of articles were hand-searched.  Researchers in the field were contacted.  Randomized trials comparing PEI or PAI with no intervention, sham intervention, other percutaneous interventions or surgery for the treatment of early HCC were considered regardless of blinding, publication status, or language.  Studies comparing RFA or combination treatments were excluded.  Two authors independently selected trials for inclusion, and extracted and analyzed data.  The hazard ratios (HRs) for median OS and recurrence-free survival were calculated using the Cox regression model with Parmar's method.  Type and number of adverse events were reported descriptively.  Three randomized trials with a total of 261 patients were eligible for inclusion.  The risk of bias was high in all trials.  Two of the trials compared PEI with PAI.  Overall survival (HR 1.47; 95 % CI: 0.68 to 3.19) and recurrence-free survival (HR 1.42; 95 % CI: 0.68 to 2.94) were not significantly different.  Data on the duration of hospital stay were inconclusive.  Data on quality of life were not available.  There were only mild adverse events in both treatment modalities.  The other trial compared PEI with surgery.  There was no significant difference in overall survival (HR 1.57; 95 % CI: 0.53 to 4.61) and recurrence-free survival (HR 1.35; 95 % CI: 0.69 to 2.63).  No serious adverse events were reported in the PEI group.  Three post-operative deaths occurred in the surgery group.  The authors concluded that PEI and PAI does not differ significantly regarding benefits and harms in patients with early HCC, but only a limited number of patients have been examined and the bias risk was high in all trials.  There is also insufficient evidence to determine whether PEI or segmental liver resection is more effective, although PEI may seem safer.

In a meta-analysis, Wang et al (2010) identified the survival benefits of TACE combined with percutaneous ablation (PA) therapy (RFA or PEI) for unresectable HCC compared with those of TACE or PA alone.  Randomized-controlled trials (RCTs) published as full papers or abstracts were searched to assess the survival benefit or tumor recurrence for patients with unresectable HCC on electronic databases.  The primary outcome was survival.  The secondary outcomes were response to therapy and tumor recurrence.  A total of 10 RCTs met the criteria to perform a meta-analysis including 595 participants.  Transcatheter arterial chemoembolization combined with PA therapy, respectively improved, 1-, 2-, and 3-year OS compared with that of monotherapy [odds ratio (OR) = 2.28, 95 % CI: 1.14 to 4.57; p = 0.020], (OR = 4.53, 95 % CI: 2.62 to 7.82, p < 0.00001) and (OR = 3.50, 95 % CI: 1.75 to 7.02, p = 0.0004).  Sensitivity analysis demonstrated a significant benefit in 1-, 2- and 3-year OS of TACE plus PEI compared with that of TACE alone for patients with large HCC lesions, but not in TACE plus RFA versus RFA for patients with small HCCs.  The pooled result of 5 RCTs showed that combination therapy decreased tumor recurrence compared with that of monotherapy (OR = 0.45, 95 % CI: 0.26 to 0.78, p = 0.004).  The authors concluded that TACE combined with PA therapy especially PEI improved the OS status for large HCCs.

Hepatic arterial infusion (HAI) of chemotherapy involves the use of an implanted subcutaneous pump to deliver continuous chemotherapy into the hepatic artery.  Controlled trials have shown that this therapy is associated with higher tumor response rates and this approach is considered a potentially curative treatment of patients with colorectal cancer (CRC) with isolated liver metastases.  Other applications of intra-hepatic chemotherapy are unproven.

Mocellin et al (2007) stated that the treatment of unresectable liver-confined metastatic disease from CRC is a challenging issue.  Although loco-regional treatments such as HAI claim the advantage of delivering higher doses of anti-cancer agents directly into the affected organ, the benefit in terms of OS is unclear.  These investigators quantitatively summarized the results of RCTs comparing HAI with systemic chemotherapy (SCT).  They reported that 10 RCTs have been published for a total of 1,277 patients.  For tumor response rates, relative risks (RR) and their 95 % CIs were obtained from raw data; for OS, HRs and their 95 % CIs were extrapolated from the Kaplan-Meier survival curves.  These researchers noted that HAI regimens were based on floxuridine (FUDR) in 9 of 10 RCTs, whereas in 1 RCT, fluorouracil (FU) + leucovorin was used.  Systemic chemotherapy consisted of FUDR, FU, FU + leucovorin, or a miscellany of FU and best supportive care in 3, 1, 4, and 2 studies, respectively.  Pooling the data, tumor response rate was 42.9 % and 18.4 % for HAI and SCT, respectively (RR = 2.26; 95 % CI, 1.80 to 2.84; p < 0.0001).  Mean weighted median OS times were 15.9 and 12.4 months for HAI and SCT, respectively; the meta-risk of death was not statistically different between the 2 study groups (HR = 0.90; 95 % CI, 0.76 to 1.07; p = 0.24).  The authors concluded that currently available evidence does not support the clinical or investigational use of fluoropyrimidine-based HAI alone for the treatment of patients with unresectable CRC liver metastases, at least as a first-line therapy.

In a review on recent advances in transarterial therapy of primary and secondary liver malignancies, Kalva and colleagues (2008) stated that transarterially administered gene therapy holds promise but is still in the early stages of investigation.

Despite various modalities available for the treatment of non-resectable HCC, such therapies have not resulted in marked impact on OS.  A new approach in treating these patients is administration of microspheres via hepatic artery branches with subsequent deposition in the tumor terminal vasculature.  This method could provide an approximately 3-fold or greater radiation dose in tumor nodules relative to normal liver.  Previous studies have demonstrated that yttrium-90 embedded into non-biodegradable glass microspheres (TheraSphere, MDS Nordion Inc., Kanata, Ontario, Canada) can be administered safely by intra-hepatic arterial injection to patients with HCC and underlying cirrhosis at a dose of 100 Gy.  A recent study (Dancey et al, 2000) reported that intra-hepatic yttrium-90 microspheres appears to be beneficial for patients with non-resectable HCC with less toxicity than systemic or hepatic arterial chemotherapy or hepatic arterial chemoembolization.

Dancey et al (2000) indicated that the following criteria be used to select appropriate patients for administration of intra-hepatic microspheres as an adjuvant to chemotherapy, surgery or transplantation for persons with unresectable HCC.  These criteria are based on the selection criteria for clinical studies of the TheraSphere submitted for FDA approval, and contraindications to use of TheraSphere in the FDA-approved product labeling.  These criteria may also be applied to persons with metastatic liver tumors from primary CRC (see discussion of SIR-Spheres below): 

  1. Histologically confirmed non-resectable lesion confined to the liver and at least 1 measurable lesion; and 
  2. Eastern Cooperative Oncology Group (ECOG) performance status score less than or equal to 3

    1. Absolute granulocyte count greater than or equal to 2.0 x 10 9/L
    2. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) less than 5 x upper normal limit [AST = 5 to 40 IU/L, ALT = 5 to 35 IU/L, ALP = 42 to 128 U/L]
    3. Bilirubin less than 1.5 x upper normal limit [total bilirubin = 0.1 to 1.0 mg/dL or 5.1 to 17.0 mmol/L]
    4. Estimated life expectancy greater than or equal to 12 weeks
    5. Normal pulmonary function defined as within 30 % of the expected values for each parameter (e.g., forced vital capacity, forced expiratory volume in 1 second, maximal mid-expiratory flow, maximal voluntary ventilation, and arterial blood gases);
    6. Platelet count greater than or equal to 100 x 109/L
    7. Prothrombin time (PT) and activated partial prothrombin time (APTT) within normal limits [PT = 11.0 to 12.5 seconds; APTT = 30 to 40 seconds]; and

  3. Adequate bone marrow and hepatic function; and 
  4. No contraindications to hepatic artery catheterization (e.g., vascular abnormalities, bleeding diathesis, allergy to contrast dye, or portal vein thrombosis); and 
  5. No other concurrently planned oncotherapy; and 
  6. At least 1 month post other chemotherapy or surgery.

The following exclusion criteria apply:  

  1. Previous chemotherapy or radiation therapy for hepatoma; or 
  2. Potential absorbed dose to lungs greater than 30 Gy; or 
  3. Any uncorrectable angiographic flow to the gastrointestinal tract; or 
  4. Co-morbid disease that would preclude safe delivery of intra-hepatic microspheres treatment and place the member at undue risk.  

Diagnostic work-up prior to the use of intra-hepatic microspheres includes (i) hepatic angiogram which entails placement of intra-hepatic catheter to assess vasculature and TheraSphere delivery route, and (ii) technetium-99 macroaggregated albumin (Tc-99 MAA) study to evaluate hepatic flow to gastrointestinal tract and/or pulmonary shunting.  These studies are medically necessary and thus are eligible for coverage.

In the United States, SIR-Spheres are indicated for the treatment of unresectable metastatic liver tumors from primary CRC with adjuvant intra-hepatic artery chemotherapy (IHAC) of FUDR (floxuridine).  The Food and Drug Administration (FDA) approval of SIR-Spheres was based on the results of a RCT involving 70 persons with CRC metastatic to the liver, 34 of whom received FUDR chemotherapy (control group), and 36 of whom received FUDR plus SIR-Spheres.  Two of the patients receiving FUDR plus SIR-Spheres had a CR, and 16 had a partial response (PR).  By comparison, 1 patient receiving FUDR alone achieved a CR and 7 had a PR.  There is a statistically significant delay of time to progression of the disease in the group treated with FUDR plus SIR-Spheres, when compared with the group treated with FUDR only.

The FDA-approved product labeling for SIR-Spheres states that treatment with SIR-Spheres may be indicated when the metastatic CRC in the liver is considered unresectable.  According to the FDA-approved labeling, metastatic CRC may be considered non-resectable in any of the following circumstances:

  1. Multiple liver metastases together with involvement of both lobes; or
  2. Tumor invasion of the hepatic confluence where the 3 hepatic veins enter the inferior vena cava (IVC) such that none of the hepatic veins could be preserved if the metastases were resected; or
  3. Tumor invasion of the porta hepatis such that neither origin of the right or left portal veins could be preserved if resection were undertaken; or
  4. Widespread metastases such that resection would require removal of more liver than is necessary to maintain life.

The FDA-approved product labeling for SIR-Sphere’s states that resectability may be evaluated via imaging with a triple phase contrast angio-portal CT scan or MRI.

The FDA-approved labeling for SIR-Sphere states that the following tests are recommended before treatment.

  1. A hepatic angiogram should be performed to establish arterial anatomy of the liver.
  2. A nuclear medicine break-through scan (intra-hepatic technetium MAA Scan) to determine the percent lung shunting.  If a port has been inserted, this test can be performed through the port.
  3. Serologic tests of liver function should be performed to determine the extent of liver function/damage.

The FDA-approved product labeling for SIR-Spheres states that appropriate imaging studies are recommended to determine the extent of disease.  These may include chest x-ray, CT scan of chest and abdomen, abdominal ultrasound and a bone scan.

The product labeling states that SIR-Spheres are contraindicated in patients who have

  • Ascites or are in clinical liver failure, or
  • Been treated with capecitabine within the 2 previous months, or who will be treated with capecitabine at any time following treatment with SIR-Spheres, or
  • Disseminated extra-hepatic malignant disease, or
  • Greater than 20 % lung shunting of the hepatic artery blood flow determined by technetium MAA scan, or
  • Had previous external beam radiation therapy to the liver, or
  • Markedly abnormal synthetic and excretory liver function tests (LTFs), or
  • Portal vein thrombosis; or
  • Pre-assessment angiogram that demonstrates abnormal vascular anatomy that would result in significant reflux of hepatic arterial blood to the stomach, pancreas or bowel.

The manufacturer of SIR-Spheres recommends a SPECT scan of the upper abdomen be performed immediately after implantation of SIR-Spheres to confirm placement of the microspheres in the liver.

An assessment by the California Technology Assessment Forum (Tice, 2009) on selective internal radiation therapy or radioembolization for inoperable liver metastases from colorectal cancer reported that 22 case series with data on patients with metastatic CRC have demonstrated that it is feasible to deliver radiation therapy to liver tumors and achieve at least partial remission in a substantial proportion of patients with relatively few serious adverse events.  The assessment stated that procedure-specific adverse events such as radiation pneumonitis, gastrointestinal ulceration and radiation-induced liver disease have been characterized and pre-treatment planning strategies have been developed to limit their frequency and severity. The CTAF assessment (Tice, 2009) reported that results of 2 RCTs (citing Gray et al, 2001; van Hazel et al, 2004) are encouraging, but not definitive.  Both trials demonstrated improvements in disease-free survival and a trend towards longer OS.  However, the trials were very small (less than 100 patients in total) and the response rates in the control groups were lower than expected.  Furthermore, the assessment noted, the control groups did not use the standard first-line therapy for CRC metastatic only to the liver.  The assessment stated that ongoing clinical trials that are randomizing over 800 newly diagnosed patients to first line chemotherapy with or without radioembolization should define the efficacy of combined therapy and the associated additional toxicity.  Similarly, the data on the utility of radioembolization as salvage therapy for patients who have failed multiple rounds of chemotherapy is limited and immature.

Guidelines from the National Comprehensive Cancer Network (NCCN, 2009) state that radioembolization is an acceptable alternative for management of unresectable liver only or liver dominant metastases from carcinoids or islet cell tumors.

Guidance from the National Institute for Health and Clinical Excellence (2011) concluded that current evidence on the safety of selective internal radiation therapy for non-resectableccolorectal metastases in the liver is adequate. The report concluded, however, that the evidence on its efficacy in chemotherapy-naive patients is inadequate in quantity. The report found that, for patients who have previously been treated with chemotherapy, there is evidence that selective internal radiation therapy can prolong time to progression of hepatic metastases, but more evidence is required on survival and quality of life. Therefore for patients who have been previously treated with chemotherapy this procedure should be used with special arrangements for clinical governance, consent and audit. The NICE Committee considered selective internal radiation therapy a potentially beneficial treatment for patients with non-resectable colorectal metastases in the liver, but concluded that more research and data collection are required to demonstrate its efficacy. The Committee noted that observational studies report large numbers of patients previously treated by chemotherapy who have received selective internal radiation therapy, but that the number of these patients reported in comparative trials was very small. For patients who have previously been treated with chemotherapy, comparative trials are needed to determine whether selective internal radiation therapy prolongs survival compared with best standard treatment, and to determine its effect on quality of life. There is also a need to identify which subgroups of patients are likely to derive clinical benefit from selective internal radiation therapy. The NICE Committee noted that there have been a small number of reports of SIRT downstaging colorectal metastases to the extent that treatment by resection or ablation became possible. However, it considered that there was insufficient evidence to comment on the potential use of the procedure with this intent.

The advantage of chemoembolization of the liver as an anti-neoplastic treatment for HCC is that it achieves high intra-tumoral concentrations of the chemotherapeutic agent locally that can not be reached with systemic chemotherapy in non-toxic doses.  However, chemotherapeutic release and local concentrations can not be standardized by this technique.  Drug-eluting beads (DEB) are believed to have predictable pharmacokinetics and can achieve higher doses of the chemotherapeutic and prolonged contact time with cancer cells.

In a phase I/II clinical trial, Poon and colleagues (2007) assessed the safety and efficacy of TACE using doxorubicin-eluting beads (DC Beads) for HCC.  Patients with incurable HCC and Child-Pugh class A cirrhosis were considered eligible.  Two courses of TACE using DC Beads were given at an interval of 2 months, and tumor response was assessed by computerized tomography scan.  The phase I trial was a dose-escalating study starting from 25 mg to 150 mg doxorubicin in cohorts of 3 patients.  The 150-mg doxorubicin dose was used for the phase II study.  Primary end points were treatment-related complications and deaths.  Secondary end points included tumor response and pharmacokinetics of doxorubicin.  In the phase I study involving 15 patients, no dose-limiting toxicity was observed for up to 150 mg doxorubicin, which was used for 20 patients in the phase II study.  The pharmacokinetic study showed a low peak plasma doxorubicin concentration (49.4 +/- 23.7 ng/ml), and no systemic toxicity was observed.  The treatment-related complication rate was 11.4 %.  There was no treatment-related death.  Among 30 patients who completed 2 courses of TACE, the PR rate and the CR rates were 50 % and 0 %, respectively, by response evaluation criteria in solid tumors (RECIST) criteria at computerized tomography scan 1 month after the second TACE.  By modified RECIST criteria, taking into account the extent of tumor necrosis, 19 (63.3 %) patients had a PR and 2 (6.7 %) had a CR.  The authors concluded that these findings showed that TACE using DC Beads is a safe and effective treatment for HCC, supporting a phase III randomized trial to compare this novel treatment with conventional TACE using doxorubicin-lipiodol emulsion.

In an open-label, single-center, single-arm study, Malagari et al (2008) evaluated the safety and efficacy of DC Beads delivered by TACE for the treatment of unresectable HCC.  A total of 62 cirrhotic patients with documented single unresectable HCC were included in this study.  Mean tumor diameter was 5.6 cm (range of 3 to 9 cm) classified as Okuda stages 1 (n = 53) and 2 (n = 9).  Patients received repeat embolizations with DC Beads every 3 months (maximum of 3).  The maximum doxorubicin dose was 150 mg per embolization, loaded in DC Beads of 100 to 300 or 300 to 500 microm.  Regarding efficacy, overall, an objective response according to the European Association for the Study of the Liver (EASL) criteria was observed in 59.6 %, 81.8 %, and 70.8 % across 3 treatments.  A CR was observed in 4.8 % after the first procedure and 3.6 % and 8.3 % after the second and third procedures, respectively.  At 9 months a CR was seen in 12.2 %, an objective response in 80.7 %, progressive disease in 6.8 %, and 12.2 % showed stable disease.  Mean tumor necrosis ranged from 77.4 % to 83.9 % (range of 28.6 % to 100 %) across 3 treatments.  Alpha-fetoprotein levels showed a mean decrease of 1,123 ng/ml (95 % CI: 846 to 1399; p = 3 x 10(-11)) after the first session and remained stable after the second and third embolizations (42 and 70 ng/ml decrease, respectively).  Regarding safety, bilirubin, gamma-glutamyl transferase, aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase showed only transient increases during the study period.  Severe procedure-related complications were seen in 3.2 % (cholecystitis, n = 1; liver abscess, n = 1).  Post-embolization syndrome was observed in all patients.  The authors concluded that CE using doxorubicin-loaded DC Beads is a safe and effective treatment of HCC as demonstrated by the low complication rate, increased tumor response, and sustained reduction of alpha-fetoprotein levels.

Carter and Martin (2009) stated that DEB-TACE is a novel therapy for the treatment of hyper-vascuarized tumors.  Through the intra-arterial delivery of microspheres, DEB-TACE allows for embolization as well as local release of chemotherapy in the treatment of hepatic malignancy, providing an alternative therapeutic option in unresectable tumors.  Its role as an adjunct to surgical resection or RFA is less clear.   These researchers summarized recent studies investigating DEB-TACE in order to better define safety, efficacy and outcomes associated with its use.  A systematic review of all published articles and trials identified 9 clinical trials and 23 abstracts.  These were reviewed for tumor histology, stage of treatment, delivery technique, outcome at follow-up, complications and mortality rates.  Publications involved treatment of HCC, metastatic colorectal carcinoma (MCRC), metastatic neuroendocrine (MNE) disease and cholangiocarcinoma (CCA).  Using RECIST or EASL criteria, studies treating HCC reported CR rates of 5 % (5/101) at 1 month, 9 % (8/91) at 4 months, 14 % (19/138) at 6 months and 25 % (2/8) at 10 months; PR was reported as 58 % (76/131) at 1 month, 50 % (67/119) at 4 months, 57 % (62/108) at 6-7 months and 63 % (5/8) at 10 months.  Studies involving MCRC, CCA and MNE disease were less valuable in terms of response rate because there is a lack of comparative data.  The most common procedure-associated complications included fever (46 to 72 %), nausea and vomiting (42 to 47 %), abdominal pain (44 to 80 %) and liver abscess (2 to 3 %).  Rather than reporting individual symptoms, 2 studies reported rates of post-embolic syndrome, consisting of fever, abdominal pain, and nausea and vomiting, at 82 % (75/91).  Six of 8 studies reported length of hospital stay, which averaged 2.3 days per procedure.  Mortality was reported as occurring in 10 of 456 (2 %) procedures, or 10 of 214 (5 %) patients.  The authors concluded that drug-eluting bead TACE is becoming more widely utilized in primary and liver-dominant metastatic disease of the liver.  Outcomes of success must be expanded beyond response rates because these are not a reliable surrogate for progression-free survival or OS.  Ongoing clinical trials will further clarify the optimal timing and strategy of this technology.

In a phase II clinical trial, Fiorentini et al (2009) evaluated the safety and efficacy of TACE.  A total of 10 patients with liver metastases (LM) from uveal melanoma (UM) were treated with TACE-containing beads pre-loaded with irinotecan (IRI, 100 mg).  All patients had an objective response, 3 presented a very good PR and 7 obtained a PR.  The median follow-up time from the beginning of therapy was 6.5 months (range of 4 to 9 months); 8 patients were alive at the time of this analysis.  The most important adverse event was abdominal pain during the procedure.  Adequate supportive treatment with antibiotic and anti-emetic prophylaxis, desametazone and intravenous hydration is strictly necessary until stabilization of serum levels of transaminases and to prevent infections.  A major analgesic such as morphine must be used before and after the procedure.  The authors concluded that TACE containing beads pre-loaded with IRI is effective in the treatment of LM from UM.  This approach seems to have better efficacy than previous TACE regimens adopted.

In an open-label, multi-center, single-arm study, Martin et al (2009) examined the value of DEB in patients with unresectable colorectal hepatic metastasis who had failed standard therapy.  Patients received repeat embolizations with IRI-loaded beads (max 100 mg per embolization) per treating physician's discretion.  A total of 55 patients underwent 99 treatments using IRI-DEB.  The median number of total treatments per patient was 2 (range of 1 to 5).  Median length of hospital stay was 23 hours (range of 23 hours to 10 days).  There were 30 (30 %) sessions associated with adverse reactions during or after the treatment.  The median disease free and OS from the time of first treatment was 247 days and 343 days.  Six patients (10 %) were down-staged from their original disease status.  Of these, 4 were treated with surgery and 2 with RFA.  Neither number of liver lesions, size of liver lesions or extent of liver replacement (less than or equal to 25 % versus greater than 25 %) were predictors of OS.  Only the presence of extra-hepatic disease (p = 0.001), extent of prior chemotherapy (failed 1st and 2nd line versus greater than 2 line failure) (p = 0,007) were predictors of OS in multi-variate analysis.  The authors concluded that the findings in this interim report indicated that CE using IRI-loaded beads was safe and effective in the treatment of patients as demonstrated by a minimal complication rate and acceptable tumor response.

In a pilot study, Guiu et al (2009) evaluated efficacy and toxicity of a TACE procedure using a combination of pirarubicin, amiodarone, lipiodol, and gelatin sponge.  A total of 43 patients were included in this study and they underwent TACE for unresectable HCC.  Computed tomography scans were performed to assess tumor response (RECIST) and lipiodol uptake after the first session.  Median follow-up lasted 30 months.  Endpoints were OS and progression-free survival.  Survival was estimated using Kaplan Meier estimations and compared using log-rank tests.  Uni-variate and multi-variate Cox analyses were used to calculate HRs with their 95 % CI.  Twenty-seven (67.5 %) patients had alcoholic cirrhosis.  Mean tumor size was 9.5 cm (1 to 20 cm) and 37/43 were multi-focal or diffuse.  Cancer of the liver Italian program score was 0 in 7/40 and 1 in 16/40.  Mean number of TACE sessions was 3.5 (1 to 11).  There were 3 treatment-related deaths (2 severe sepsis, 1 bowel perforation).  A PR and a stable disease were observed in 12 (28 %) and 29 (67 %) patients, respectively.  Median OS and progression-free survival were 29 months (95 % CI: 13.8 to 45) and 15 months (95 % CI: 11.5 to 20.8), respectively.  Cancer of the liver Italian program score less than or equal to 1 (p = 0.042) and lipiodol uptake greater than 25 % (p = 0.003) were independent prognostic factors for better OS.  The authors concluded that this new TACE procedure is safe with a high OS rate and certainly deserves phase III investigation to compare it with classic treatments such as doxorubicin-lipiodol TACE.

Tokh et al (2010) noted that conventional TACE uses a combination of chemotherapy, lipiodol, and an embolic agent.  Drug-eluting bead therapy is a potentially less toxic and therapeutically equivalent form of intra-arterial drug delivery.  These researchers assessed the safety, efficacy and survival among patients with HCC treated with DEB after a long experience with traditional TACE.  A total of 63 sequential patients with unresectable HCC were treated over an 18-month period.  Subjects received 2 courses of DEB-CE, using 100 mg doxorubicin in DEB ranging from 300 to 700 microns in diameter.  They retrospectively analyzed patient demographics, etiologies of liver disease, Child Pugh status, CLIP scores, size of largest tumor, baseline alpha-fetoprotein (AFP), toxicity, change in size of largest tumor, change in AFP, and survival from first treatment.  A total of 63 patients (51 men; median age of 62 years) were treated; 53 had cirrhosis (30 Hepatitis C, 12 from alcohol); 6 had portal vein thrombosis; median tumor size was 4.8 cm (range of 2 to 12 cm); 37 had elevated AFP (median 471 ng/ml, range of 21 to 54,860). 37 were Child's A and 26 B; 9 had CLIP scores greater than 2. 51 remain alive, and 30-day mortality was zero.  Most common adverse reactions were abdominal pain (71 %), nausea (52 %), and fatigue (18 %).  Overall, 81 % of evaluable patients had tumor regression; AFP decreased in 79 % of patients with elevated levels, with a median fall of 78.5 %.  Poor prognostic indicators for survival following the procedure included cirrhosis, elevated bilirubin and elevated AFP; CLIP score, Child's status, etiology and size did not significantly impact outcome.  Actuarial survival was 18.2 months.  The authors concluded that outcomes following treatment of HCC using DEB compare favorably with historic results using conventional CE.  Patients experience substantially less fever, a shorter duration of pain, but more nausea within 24 hours.  There were no early deaths.  Survival appears to be at least equivalent, with milder toxicity, compared with the authors' historic experience.  They noted that RCTs of the 2 modalities of CE are currently under way.

Malagari et al (2010) evaluated the added role of a chemotherapeutic in TACE of intermediate-stage HCC.  The issue is of major importance since, as suggested by recent evidence, hypoxia or incomplete de-vascularization of the tumor is a potent stimulator of angiogenesis, and there are not many papers supplying level one evidence confirming the value of a chemotherapeutic.  The hypothesis was that since DEB-TACE is standardized and reproducible, a comparison with bland TACE can readily reveal the potential value of the chemotherapeutic.  In this prospective study, 2 groups were randomized : group A (n = 41) was treated with doxorubicin DEB-TACE, and group B (n = 43) with bland embolization.  Patients were randomized for tumor diameter; they were embolized at set time intervals (2 months), with a maximum of 3 embolizations.  Tumor response was evaluated using the EASL criteria and AFP levels.  At 6 months a CR was seen in 11 patients (26.8 %) in the DEB-TACE group and in 6 patients (14 %) in the bland embolization group; a PR was achieved in 19 patients (46.3 %) and 18 (41.9 %) patients in the DEB-TACE and bland embolization groups, respectively.  Recurrences at 9 and 12 months were higher for bland embolization (78.3 % versus 45.7 %) at 12 months.  Time to progression (TTP) was longer for the DEB-TACE group (42.4 +/- 9.5 and 36.2 +/- 9.0 weeks), at a statistically significant level (p = 0.008).  The authors concluded that DEB-TACE presents a better local response, fewer recurrences, and a longer TTP than bland embolization with BeadBlock.  However, survival benefit and bland embolization with smaller particles must be addressed in future papers to better assess the clinical value.

Nicolini et al (2010) retrospectively compared radiological tumor response and degree of necrosis in explanted livers after CE with epirubicin-loaded DC Bead versus bland embolization in patients on a transplant waiting list.  From 2003 to 2007, 49 patients with HCC underwent transplantation at a single center.  Sixteen patients were treated with bland embolization (n = 8) with 100-300-microm Embosphere particles or CE with epirubicin-loaded 100-300-microm DC Bead particles (n = 8) every other month until complete tumor de-vascularization.  Computed tomography was performed every 3 months until recurrence.  Explanted livers were analyzed to evaluate the degree of necrosis in the nodules.  After orthotopic liver transplantation (OLT), patients were followed-up for survival and disease status.  The groups were comparable for baseline characteristics.  Most patients had Child-Pugh class A disease.  Solitary HCC was found in 75 % of patients.  Mean target lesion size was 32 mm +/- 15.4.  Chemoembolization with DEB achieved complete necrosis in 77 % of lesions whereas bland embolization achieved complete necrosis in 27.2 % of lesions.  There was a significant difference between bland embolization and CE with DEB with regard to histological necrosis (p = 0.043).  No significant treatment-related complications were observed for either group.  Fifteen patients are alive with no tumor recurrence.  The authors concluded that CE with DEB before OLT achieved higher rates of complete histological response than bland embolization, with no serious adverse events observed.  Because of the retrospective data analyses and small sample size, further studies are warranted to confirm these promising results.

Current NCCN guidelines on cervical cancer include no recommendation to use chemoembolization for cervical cancer, including cervical cancers metastatic to the liver.  In addition, National Cancer Institute (PDQ) guidance includes no recommendation for chemoembolization for liver cancer.  ClinicalTrials.gov lists dozens of trials of chemoembolization, primarily for hepatocellular carcinoma and for colorectal cancers metastatic to the liver.  However, there are no trials listed in ClinicalTrials.gov for chemoembolization for persons with cervical cancer.  Peer-reviewed published evidence for chemoembolization for cervical cancer consists of 3 retrospective case-series studies (in Chinese – Liu et al, 2009; Yu et al, 2009; and Tian et al, 2010).  The largest of these (Tian et al, 2010) found no improvements in survival with the addition of chemoembolization to radiotherapy for cervical cancer.  The study concluded that “Compared with the simple radiotherapy, there are a similar short-term survival rate and significant poor 5-year, 8-year survival rate in the patients treated with the uterine arterial interventional chemoembolization combined with radiotherapy, which also may be strong dangerous factor for the occurrence of tardive bladder injury.  The results shown that the uterine arterial interventional chemoembolization do not recommend to be routine adjuvant therapy for the radical radiotherapy of cervical cancer”.

 
CPT Codes / HCPCS Codes / ICD-9 Codes
CPT codes covered if selection criteria are met:
36245
36260
37242
37243
75894
75896
77750
77776 - 77778
96446
Other CPT codes related to the CPB:
96522
HCPCS codes covered if selection criteria are met:
C2616 Brachytherapy source, nonstranded, yttrium-90, per source [microspheres]
Q3001 Radioelements for brachytherapy, any type, each
S2095 Transcatheter occlusion or embolization for tumor destruction, percutaneous, any method, using yttrium-90 microspheres
Other HCPCS codes related to the CPB:
J2353 Injections, octreotide, depot form for intramuscular injection, 1 mg
J2354 Injections, octreotide, non-depot form for subcutaneous intravenous injection, 25 mcg
Percutaneous Ethanol Injection:
ICD-9 codes covered if selection criteria are met:
155.0 Malignant neoplasm of the liver, primary [hepatocellular cancers (HCC) without extrahepatic spread]
ICD-9 codes not covered for indications listed in the CPB:
155.2 Malignant neoplasm of the liver, not specified as primary or secondary
197.7 Secondary malignant neoplasm of liver, specified as secondary
Chemoembolization:
ICD-9 codes covered if selection criteria are met:
155.0 - 155.2 Malignant neoplasm of the liver and intrahepatic bile ducts [unresectable]
157.0 - 157.9 Malignant neoplasm of pancreas [endocrine involving the liver] [in persons who have failed systemic therapy with octreotide to control carcinoid syndrome (e.g., debilitating flushing, wheezing, and diarrhea)]
190.0 Malignant neoplasm of eyeball except conjunctiva, cornea, retina, and choroid [with liver-only metastases]
209.00 - 209.29 Malignant carcinoid tumors
209.72 Secondary neuroendocrine tumor of liver
V49.83 Awaiting organ transplant status [Preoperative hepatic artery chemoembolization followed by orthotopic liver transplantation for HCC}
ICD-9 codes not covered for indications listed in the CPB:
153.0 - 153.9 Malignant neoplasm of colon
171.0 - 171.9 Malignant neoplasm of connective tissue and other soft tissue [rhabdomyosarcoma]
172.0 - 172.9 Malignant melanoma of skin
174.1-174.9 Malignant Neoplasm of Female Breast
175.0-175.9 Malignant Neoplasm of Male Breast
197.7 Secondary malignant neoplasm of liver, specified as secondary [palliative treatment of liver metastases from other non-neuroendocrine primaries (e.g., colon cancer, melanoma, or unknown primaries)]
199.1 Other malignant neoplasm without specification of site [unknown primary]
V10.3 Personal history of malignant neoplasm of breast
Intra-hepatic chemotherapy:
ICD-9 codes covered if selection criteria are met:
153.0 - 154.8 Malignant neoplasm of colon, rectum, rectosigmoid junction, and anus [not covered for "one-shot" arterial chemotherapy or transarterial gene therapy]
ICD-9 codes not covered for indications listed in the CPB:
155.0 - 155.2 Malignant neoplasm of the liver and intrahepatic bile ducts [liver primary]
Intra-hepatic microspheres:
ICD-9 codes covered if selection criteria are met:
153.0 - 154.8 Malignant neoplasm of colon, rectum, rectosigmoid junction, and anus [unresectable liver tumors from primary colorectal cancer]
155.0 - 155.2 Malignant neoplasm of the liver and intrahepatic bile ducts [unresectable primary HCC}
156.0 Malignant neoplasm of gallbladder
157.0 - 157.9 Malignant neoplasm of pancreas [endocrine tumors involving the liver and functional neuroendocrine cancers] [carcinoid tumors in persons who have failed systemic therapy with octreotide to control carcinoid syndrome (e.g., debilitating flushing, wheezing and diarrhea)]
197.8 Secondary malignant neoplasm of other digestive organs and spleen
209.00 - 209.29 Malignant carcinoid tumors [functional neuroendocrine cancers in persons who have failed systemic therapy with octreotide to control carcinoid syndrome (e.g., debilitating flushing, wheezing and diarrhea)]
209.72 Secondary neuroendocrine tumor of liver
Drug-Eluting Beads Trans-Arterial Chemoembolization:
ICD-9 codes not covered for indications listed in the CPB:
155.0 - 155.2 Malignant neoplasm of the liver and intrahepatic bile ducts
171.0 - 171.9 Malignant neoplasm of connective tissue and other soft tissue [leiomyosarcoma]
197.7 Secondary malignant neoplasm of liver, specified as secondary [liver dominant]
Other ICD-9 codes related to the CPB:
259.2 Carcinoid syndrome
782.62 Flushing
786.07 Wheezing
787.91 Diarrhea


The above policy is based on the following references:

Percutaneous Ethanol Injection

  1. Livraghi T, Bolondi L, Lazzaroni S, et al. Percutaneous ethanol injection in the treatment of hepatocellular carcinoma in cirrhosis. Cancer. 1992;69:925-929.
  2. Shiina S, Niwa Y, Omata M. Percutaneous ethanol injection therapy for liver neoplasms. Sem Interven Radiol. 1993;10:57-68.
  3. Tanikawa K. Non-invasive loco-regional therapy for hepatocellular carcinoma. Semin Surg Oncol. 1996;12(3):189-192.
  4. Bartolozzi C, Lencioni R. Ethanol injection for the treatment of hepatic tumours. Eur Radiol. 1996;6(5):682-696.
  5. Liu CL, Fan ST. Nonresectional therapies for hepatocellular carcinoma. Am J Surg. 1997;173(4):358-365.
  6. Lin DY, Lin SM, Liaw YF. Non-surgical treatment of hepatocellular carcinoma. J Gastroenterol Hepatol. 1997;12(9-10):S319-S328.
  7. Colombo M. Treatment of hepatocellular carcinoma. J Viral Hepat. 1997;4(suppl 1):125-130.
  8. Corabian P. Percutaneous ethanol injection therapy as a treatment for hepatic cancer. HTB2. Edmonton, AB: Alberta Heritage Foundation for Medical Research (AHFMR): May 1997.
  9. Mathurin P, Rixe O, Carbonell N, et al. Overview of medical treatments in unresectable hepatocellular carcinoma - An impossible meta-analysis?. Aliment Pharmacol Therapeut. 1998;12(2):111-126.
  10. Mor E, Kaspa RT, Sheiner P, Schwartz M. Treatment of hepatocellular carcinoma associated with cirrhosis in the era of liver transplantation. Ann Intern Med. 1998;129(8):643-653.
  11. Masaki T, Morishita A, Kurokohchi K, Kuriyama S. Multidisciplinary treatment of patients with hepatocellular carcinoma. Expert Rev Anticancer Ther. 2006;6(10):1377-1384.
  12. Brunello F, Veltri A, Carucci P, et al. Radiofrequency ablation versus ethanol injection for early hepatocellular carcinoma: A randomized controlled trial. Scand J Gastroenterol. 2008;43(6):727-735.
  13. Wong SN, Lin CJ, Lin CC, et al. Combined percutaneous radiofrequency ablation and ethanol injection for hepatocellular carcinoma in high-risk locations. AJR Am J Roentgenol. 2008;190(3):W187-W195.
  14. Orlando A, Leandro G, Olivo M, et al. Radiofrequency thermal ablation vs. percutaneous ethanol injection for small hepatocellular carcinoma in cirrhosis: Meta-analysis of randomized controlled trials. Am J Gastroenterol. 2009;104(2):514-524.
  15. Germani G, Pleguezuelo M, Gurusamy K, et al. Clinical outcomes of radiofrequency ablation, percutaneous alcohol and acetic acid injection for hepatocelullar carcinoma: A meta-analysis J Hepatol. 2010;52(3):380-388.
  16. Schoppmeyer K, Weis S, Mössner J, Fleig WE. Percutanous ethanol injection or percutaneous acetic acid injection for early hepatocellular carcinoma. Cochrane Database Syst Rev. 2009;(3):CD006745.
  17. National Comprehensive Cancer Network (NCCN). Hepatobiliary cancers. NCCN Clinical Practice Guidelines in Oncology. v.1.2010. Jenkintown, PA: NCCN; 2010.

Chemoembolization

  1. Lyster MT, Benson AR III, Vogelzang R, Talamonti, M. Chemoembolization: Alternative for hepatic tumors. Contemp Oncol. 1993;Aug:17-28.
  2. Nakoa N, Kamino K, Miura K, et al. Recurrent hepatocellular carcinoma after partial hepatectomy: Value of treatment with transcatheter arterial chemoembolization. AJR Am J Roentgenol. 1991;156(6):1177-1179.
  3. Stefanini GF, Amorati P, Biselli M, et al. Efficacy of transarterial targeted treatments on survival of patients with hepatocellular carcinoma. Cancer. 1995;75(10):2427-2434.
  4. Lin DY, Liaw YF, Lee TY, Lai CM. Hepatic arterial embolization in patients with unresectable hepatocellular carcinoma -- A randomized controlled trial. Gastroenterol. 1988;94(2):453-456.
  5. Pelletier G, Roche A, Ink O, et al. A randomized trial of hepatic arterial chemoembolization in patients with unresectable hepatocellular carcinoma. J Hepatology. 1990;11(2):181-184.
  6. Groupe D'Etude et de Traitement du Carcinome Hepatocellulaire. A comparison of lipiodol chemoembolizations and conservative treatment for unresectable hepatocellular carcinoma. N Engl J Med. 1995;332(19):1256-1261.
  7. Carrasco CH, Charnsangavej C, Ajani J, et al. The carcinoid syndrome: Palliation by hepatic artery embolization. AJR. 1986;147(1):149-154.
  8. Ajani JA, Carrasco CH, Charnsangavej C, et al. Islet cell tumors metastatic to the liver: Effective palliation by sequential hepatic artery embolization. Ann Int Med. 1988;108(3):340-344.
  9. Drougas JG, Anthony LB, Blair TK, et al. Hepatic artery embolization for management of patients with advanced metastatic carcinoid tumors. Am J Surg. 1998;175(5):408-412.
  10. Miller CA, llison EC. Therapeutic alternatives in metastatic neuroendocrine tumors. Surg Oncol Clin N Am. 1998;7(4):863-879.
  11. Venook AP. Embolization and chemoembolization therapy for neuroendocrine tumors. Curr Opin Oncol. 1999;11(1):38-41.
  12. Bruix J, Llovet JM, Castells A, et al. Transarterial embolization versus symptomatic treatment in patients with advanced hepatocellular carcinoma: Results of a randomized, controlled trial in a single institution. Hepatology. 1998;27(6):1578-1583.
  13. Paye F, Jagot P, Vilgrain V, et al. Preoperative chemoembolization of hepatocellular carcinoma: A comparative study. Arch Surg. 1998;133(7):767-772.
  14. Pelletier G, Ducreux M, Gay F, et al. Treatment of unresectable hepatocellular carcinoma with lipiodol chemoembolization: A multicenter randomized controlled trial. J Hepatol. 1998;29(1):129-134.
  15. Oldhafer KJ, Chavan A, Fruhauf NR, et al. Arterial chemoembolization before liver transplantation in patients with hepatocellular carcinoma: Marked tumor necrosis, but no survival benefit? J Hepatol. 1998;29(6):953-959.
  16. Raoul JL, Boucher E, Kerbrat P. Nonsurgical treatment of hepatocellular carcinoma. Bull Cancer. 1999;86(6):537-543.
  17. Schmassmann A. Nonsurgical therapies for hepatocellular and cholangiocellular carcinoma. Swiss Surg. 1999;5(3):116-121.
  18. Solomon B, Soulen MC, Baum RA, et al. Chemoembolization 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(6):793-798.
  19. Rose DM, Chapman WC, Brockenbrough AT, et al. Transcatheter arterial chemoembolization as primary treatment for hepatocellular carcinoma. Am J Surg. 1999;177(5):405-410.
  20. Yamakado K, Nakatsuka A, Tanaka N, et al. Long-term follow-up arterial chemoembolization combined with transportal ethanol injection used to treat hepatocellular carcinoma. J Vasc Interv Radiol. 1999;10(5):641-647.
  21. Harnois DM, Steers J, Andrews JC, et al. Preoperative hepatic artery chemoembolization followed by orthotopic liver transplantation for hepatocellular carcinoma. Liver Transpl Surg. 1999;5(3):192-199.
  22. Di Carlo V, Ferrari G, Castoldi R, et al. Pre-operative chemoembolization of hepatocellular carcinoma in cirrhotic patients. Hepatogastroenterology. 1998;45(24):1950-1954.
  23. Fan J, Tang ZY, Yu YQ, et al. Improved survival with resection after transcatheter arterial chemoembolization (TACE) for unresectable hepatocellular carcinoma. Dig Surg. 1998;15(6):674-678.
  24. Alberta Heritage Foundation for Medical Research (AHFMR). Chemoembolization treatment for colorectal metastases to the liver. Technotes. Edmonton, AB: AHFMR; 2000.
  25. Llovet JM, Real MI, Montaña 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.
  26. Ramsey DE, Kernagis LY, Soulen MC, Geschwind JF. Chemoembolization of hepatocellular carcinoma. J Vasc Interv Radiol. 2002;13(9 Pt 2):S211-S221.
  27. Oliveri RS, Gluud C. Transcatheter arterial embolisation and chemoembolisation for hepatocellular carcinoma (Protocol for Cochrane Review). Cochrane Database Systematic Rev. 2004;(2):CD004787.
  28. Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival. Hepatology. 2003;37(2):429-442.
  29. Camma C, Schepis F, Orlando A, et al. Transarterial chemoembolization for unresectable hepatocellular carcinoma: Meta-analysis of randomized controlled trials. Radiology. 2002;224(1):47-54. 
  30. Marelli L, Stigliano R, Triantos C, et al. Transarterial therapy for hepatocellular carcinoma: Which technique is more effective? A systematic review of cohort and randomized studies. Cardiovasc Intervent Radiol. 2007;30(1):6-25.
  31. Pleguezuelo M, Marelli L, Misseri M, et al. TACE versus TAE as therapy for hepatocellular carcinoma. Expert Rev Anticancer Ther. 2008;8(10):1623-1641.
  32. Biolato M, Marrone G, Racco S, et al. Transarterial chemoembolization (TACE) for unresectable HCC: A new life begins? Eur Rev Med Pharmacol Sci. 2010;14(4):356-362.
  33. Wang W, Shi J, Xie WF. et al. Transarterial chemoembolization in combination with percutaneous ablation therapy in unresectable hepatocellular carcinoma: A meta-analysis. Liver Int. 2010;30(5):741-749.
  34. Zhong JH, Li LQ. Postoperative adjuvant transarterial chemoembolization for participants with hepatocellular carcinoma: A meta-analysis. Hepatol Res. 2010;40(10):943-953.
  35. Wang X, Li J, Peng Y, et al. Influence of preoperative transarterial chemoembolization on the prognosis for patients with resectable hepatocellular carcinoma: A meta-analysis of randomized trials. Hepato-Gastroenterol. 2011;58(107-108):869-874.
  36. Oliveri RS, Wetterslev J, Gluud C. Transarterial (chemo)embolisation for unresectable hepatocellular carcinoma. Cochrane Database Syst Rev. 2011;(3):CD004787.
  37. Liu FY, Wang MQ, et al. Ovarian artery supply is one of the factors affecting the interventional therapeutic efficacy of pelvic tumors. Zhonghua Zhong Liu Za Zhi. 2009;31(1):62-65.
  38. Yu L, Tan GS, Xiang XH, et al. Comparison of uterine artery chemoembolization and internal iliac arterial infusion chemotherapy for the combining treatment for women with locally advanced cervical cancer. Ai Zheng. 2009;28(4):402-407.
  39. Tian ZZ, Li S, Liu ML, et al. Clinical value of the comprehensive treatment in intermediate and advanced cervical cancer with uterine arterial interventional chemoembolization and radiotherapy. Zhonghua Fu Chan Ke Za Zhi. 2010;45(7):506-510.
  40. Xie F, Zang J, Guo X, et al. Comparison of transcatheter arterial chemoembolization and microsphere embolization for treatment of unresectable hepatocellular carcinoma: A meta-analysis. J Cancer Res Clin Oncol. 2012;138(3):455-462.

Intra-hepatic Chemotherapy (Infusion) for Liver Malignancies

  1. Martin JK Jr, O'Connell MJ, Wieand HS, et al. Intraarterial floxuridine vs systemic fluorouracil for hepatic metastases from colorectal cancer. Arch Surg. 1990;125(8):1022-1027.
  2. Rougier P, Laplanche A, Huguier M, et al. Hepatic arterial infusion of floxuridine in patients with liver metastases from colorectal carcinoma: Long term results of a prospective randomized trial. J Clin Oncol. 1992;10(7):1112-1118.
  3. Doci R, Bignami P, Bozzetti F, et al. Intrahepatic chemotherapy for unresectable hepatocellular carcinoma. Cancer. 1988;61(10):1983-1987.
  4. Meta-analysis Group in Cancer. Reappraisal of hepatic arterial infusion in the treatment of nonresectable liver metastases from colorectal cancer.  J Natl Cancer Inst. 1996;88(5):252-258.
  5. Durand-Zaleski I, Roche B, Buyse M, et al. Economic implications of hepatic arterial infusion chemotherapy in treatment of nonresectable colorectal liver metastases. Meta-analysis Group in Cancer. J Natl Cancer Inst. 1997;89(11):790-795.
  6. Lorenz M, Staib-Sebler E, Koch B, et al. The value of postoperative hepatic arterial infusion following curative liver resection. Anticancer Res. 1997;17(5B):3825-3833.
  7. Urabe T, Kaneko S, Matsushita E, et al. Clinical pilot study of a intrahepatic arterial chemotherapy with methotrexate, 5-fluorouralcil, cisplatin and subcutaneous interferon-alpha-2b for patients with locally advanced hepatocellular carcinoma. Oncology. 1998;55(1):39-47.
  8. Rougier P. Are there indications for intraarterial hepatic chemotherapy or isolated liver perfusion? The case of liver metastases from colorectal cancer. Recent Results Cancer Res. 1998;147:3-12.
  9. Okada S. Chemotherapy in hepatocellular carcinoma. Hepatogastroenterology. 1998;45 (Suppl 3):1259-1263.
  10. Sakai Y, Izumi N, Tazawa J, et al. Treatment for advanced hepatocellular carcinoma by transarterial chemotherapy using reservoirs or one-shot arterial chemotherapy. J Chemother. 1997;9(5):347-351.
  11. Soga K, Nomoto M, Ichida T, et al. Clinical evaluation of transcatheter arterial embolization and one-shot chemotherapy in hepatocellular carcinoma. Hepatogastroenterology. 1988;35(3):116-120.
  12. ES-Y, Chow PK-H, Tai B-C, et al. Neoadjuvant and adjuvant therapy for operable hepatocellular carcinoma. Cochrane Database Systematic Rev. 1999;(3):CD001199.
  13. Nordlinger B, Rougier P. Nonsurgical methods for liver metastases including cryotherapy, radiofrequency ablation, and infusional treatment: What's new in 2001? Curr Opin Oncol. 2002;14(4):420-423.
  14. Mocellin S, Pilati P, Lise M, Nitti D. Meta-analysis of hepatic arterial infusion for unresectable liver metastases from colorectal cancer: The end of an era? J Clin Oncol. 2007;25(35):5649-5654.
  15. Kalva SP, Thabet A, Wicky S. Recent advances in transarterial therapy of primary and secondary liver malignancies. Radiographics. 2008;28(1):101-117.
  16. Mocellin S, Pasquali S, Nitti D. Fluoropyrimidine-HAI (hepatic arterial infusion) versus systemic chemotherapy (SCT) for unresectable liver metastases from colorectal cancer. Cochrane Database Syst Rev. 2009;(3):CD007823.

Intrahepatic Microspheres (TheraSphere, SIR-Sphere)

  1. Sheperd FA, Rotstein LE, Houle S, et al. A phase I dose escalation trial of yttrium-90 microspheres in the treatment of primary hepatocellular carcinoma. Cancer. 1992;70(9):2250-2254.
  2. Lau WY, Leung WT, Ho S, et al. Treatment of inoperable hepatocellular carcinoma with intrahepatic arterial yttrium-90 microspheres: A phase I and II study. Br J Cancer. 1994;70(5):994-999.
  3. Dancey JE, Sheperd FA, Paul K, et al. Treatment of nonresectable hepatocellular carcinoma with intrahepatic 90Y-microspheres. J Nucl Med. 2000;41:1673-1681.
  4. Houle S, Yip TCK, Sheperd FA, et al. Hepatocellular carcinoma: Pilot trial of treatment with 90-yttrium microspheres. Radiology. 1989;172:857-860.
  5. Herba MJ, Thirlwell MP. Radioembolization for hepatic metastases. Semin Oncol. 2002;29(2):152-159.
  6. Gray B, Van Hazel G, Hope M, et al. Randomised trial of SIR-Spheres plus chemotherapy vs. chemotherapy alone for treating patients with liver metastases from primary large bowel cancer. Ann Oncol. 2001;12(12):1711-1720.
  7. Howard K, Stockler M. Selective internal radiation therapy for hepatic metastases using SIR-Spheres(R). MSAC Application 1034. Canberra, ACT: Medical Services Advisory Committee (MSAC); 2002.
  8. National Institute for Clinical Excellence (NICE). Selective internal radiation therapy for colorectal liver metastases. Interventional Procedure Consultation Document. London, UK: NICE; January 2004. Available at: http://www.nice.org.uk/cms/htm/default/en/IP_228/ip228consultation/article.aspx. Accessed February 5, 2004.
  9. MDS Nordion Inc. TheraSphere Yttrium-90 glass microspheres. Package Insert. Rev. 6. Kanata, ON: MDS Nordion; 1999. Available at: http://www.mds.nordion.com/therasphere/physicians/packageinsert.asp. Accessed February 5, 2005.
  10. Sirtex Medical Inc. SIR-Spheres (Yttrium-90 microspheres). Product Labeling. Rockville, MD: U.S. Food and Drug Administration, Center for Devices and Radiological Health; March 5, 2005. Available at: http://www.fda.gov/cdrh/pdf/p990065.html. Accessed February 5, 2005.
  11. National Institute for Clinical Excellence (NICE). Selective internal radiation therapy for colorectal metastases in the liver. Interventional Procedure Guidance 93. London, UK: NICE; September 2004. Available at: http://www.nice.org.uk/page.aspx?o=220841. Accessed February 21, 2005.
  12. Sato K, Lewandowski RJ, Bui JT, et al. Treatment of unresectable primary and metastatic liver cancer with yttrium-90 microspheres (TheraSphere): Assessment of hepatic arterial embolization. Cardiovasc Intervent Radiol. 2006;29(4):522-529.
  13. Kulik LM, Atassi B, van Holsbeeck L, et al. Yttrium-90 microspheres (TheraSphere) treatment of unresectable hepatocellular carcinoma: Downstaging to resection, RFA and bridge to transplantation. J Surg Oncol. 2006;94(7):572-586.
  14. Allison C. Yttrium-90 microspheres (TheraSphere® and SIR-Spheres®) for the treatment of unresectable hepatocellular carcinoma. Issues in Emerging Health Technologies Issue 102. Ottawa, ON: Canadian Agency for Drugs and Technologies in Health; September 2007. Available at: http://www.cadth.ca/media/pdf/E0038_TheraSphere_cetap_e.pdf. Accessed March 6, 2008.
  15. Whitney R, Tatum C, Hahl M, et al. Safety of hepatic resection in metastatic disease to the liver after yttrium-90 therapy. J Surg Res. 2009 Jun 12. [Epub ahead of print].
  16. Gray B, Van Hazel G, Hope M, et al. Randomised trial of SIR-Spheres plus chemotherapy vs. chemotherapy alone for treating patients with liver metastases from primary large bowel cancer. Ann Oncol. 2001;12(12):1711-1720.
  17. Van Hazel G, Blackwell A, Anderson J, et al. Randomised phase 2 trial of SIR-Spheres plus fluorouracil/leucovorin chemotherapy versus fluorouracil/leucovorin chemotherapy alone in advanced colorectal cancer. J Surg Oncol. 2004;88(2):78-85.
  18. Kalinowski M, Dressler M, König A, et al. Selective internal radiotherapy with Yttrium-90 microspheres for hepatic metastatic neuroendocrine tumors: A prospective single center study. Digestion. 2009;79(3):137-142.
  19. Kennedy AS, Dezarn WA, McNeillie P, et al. Radioembolization for unresectable neuroendocrine hepatic metastases using resin 90Y-microspheres: Early results in 148 patients. Am J Clin Oncol. 2008;31(3):271-279.
  20. King J, Quinn R, Glenn DM, et al. Radioembolization with selective internal radiation microspheres for neuroendocrine liver metastases. Cancer. 2008;113(5):921-929.
  21. Rhee TK, Lewandowski RJ, Liu DM, et al. 90Y Radioembolization for metastatic neuroendocrine liver tumors: Preliminary results from a multi-institutional experience. Ann Surg. 2008;247(6):1029-1035.
  22. Sato KT, Lewandowski RJ, Mulcahy MF, et al. Unresectable chemorefractory liver metastases: Radioembolization with 90Y microspheres--safety, efficacy, and survival. Radiology. 2008;247(2):507-515.
  23. National Comprehensive Cancer Network (NCCN). Neuroendocrine tumors. NCCN Clinical Practice Guidelines in Oncology. v.2.2009. Fort Washington, PA: NCCN; 2009.
  24. Vente MA, Wondergem M, van der Tweel I, et al. Yttrium-90 microsphere radioembolization for the treatment of liver malignancies: A structured meta-analysis. Eur Radiol. 2009;19(4):951-959.
  25. Townsend A, Price T, Karapetis C. Selective internal radiation therapy for liver metastases from colorectal cancer. Cochrane Database Syst Rev. 2009;(4):CD007045.
  26. Tice JA. Selective internal radiation therapy or radioembolization for inoperable liver metastases from colorectal cancer. A Technology Assessment. San Francisco, CA: California Technology Assessment Forum (CTAF); February 17, 2010.
  27. Nachtnebel A, Sotti G, Vitale A, Perrini MR. Selective internal radiation therapy using yttrium-90 microspheres for the treatment of primary or metastatic liver malignancies. Decision Support Document No. 47. Vienna, Austria: Ludwig Boltzmann Institut fuer Health Technology Assessment (LBI-HTA); 2011.
  28. Atukorale Y. Selective internal radiation therapy for the treatment of liver cancer (v1.0). Technology Brief. Australian Safety and Efficacy Register of New Interventional Procedures - Surgical (ASERNIP-S). Brisbane, QLD: Health Policy and Advisory Committee on Technology (HealthPACT) Australia and New Zealand, Queensland Health; August 2011.
  29. National Institute for Health and Clinical Excellence (NICE). Selective internal radiation therapy for non-resectable colorectal metastases in the liver. Interventional Procedure Guidance 401. London, UK: NICE; July 2011.

Drug-Eluting Beads Trans-Arterial Chemoembolization

  1. Poon RT, Tso WK, Pang RW, et al. A phase I/II trial of chemoembolization for hepatocellular carcinoma using a novel intra-arterial drug-eluting bead. Clin Gastroenterol Hepatol. 2007;5(9):1100-1108.
  2. Malagari K, Chatzimichael K, Alexopoulou E, et al. Transarterial chemoembolization of unresectable hepatocellular carcinoma with drug eluting beads: Results of an open-label study of 62 patients. Cardiovasc Intervent Radiol. 2008;31(2):269-280.
  3. Stewart C, Martin RCG. Drug-eluting bead therapy in primary and metastatic disease of the liver. HPB. 2009;11(7):541-550.
  4. Fiorentini G, Aliberti C, Del Conte A, et al. Intra-arterial hepatic chemoembolization (TACE) of liver metastases from ocular melanoma with slow-release irinotecan-eluting beads. Early results of a phase II clinical study. In Vivo. 2009;23(1):131-137.
  5. Martin RC, Robbins K, Tomalty D, et al. Transarterial chemoembolisation (TACE) using irinotecan-loaded beads for the treatment of unresectable metastases to the liver in patients with colorectal cancer: An interim report. World J Surg Oncol. 2009;7:80.
  6. Guiu B, Colin C, Cercueil JP, et al. Pilot study of transarterial chemoembolization with pirarubicin and amiodarone for unresectable hepatocellular carcinoma. Am J Clin Oncol. 2009;32(3):238-244.
  7. Tokh M, Nugent FW, Molgaard C, et al. Transarterial chemoembolization (TACE) with drug-eluting beads (DEB) in hepatocellular carcinoma (HCC): A large single-institution experience. 2010 Gastrointestinal Cancers Symposium, Abstract No. 248. Available at: http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=72&abstractID=1818. Accessed March 1, 2010.
  8. Malagari K, Pomoni M, Kelekis A, et al. Prospective randomized comparison of chemoembolization with doxorubicin-eluting beads and bland embolization with BeadBlock for hepatocellular carcinoma. Cardiovasc Intervent Radiol. 2010;33(3):541-551.
  9. Nicolini A, Martinetti L, Crespi S, et al. Transarterial chemoembolization with epirubicin-eluting beads versus transarterial embolization before liver transplantation for hepatocellular carcinoma. J Vasc Interv Radiol. 2010;21(3):327-332.
  10. Martin RC 2nd, Rustein L, Pérez Enguix D, et al. Hepatic arterial infusion of doxorubicin-loaded microsphere for treatment of hepatocellular cancer: A multi-institutional registry. J Am Coll Surg. 2011;213(4):493-500.
  11. Song MJ, Chun HJ, Song DS, et al. Comparative study between doxorubicin-eluting beads and conventional transarterial chemoembolization for treatment of hepatocellular carcinoma. J Hepatol. 2012;57(6):1244-1250


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