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, esophageal cancer, melanoma, rhabdomyosarcoma, or unknown primaries) and CE 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 (e.g., breast) 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. For unresectable and chemo-refractory intra-hepatic cholangiocarcinoma if member exhibits liver metastases only and has an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or better with adequate liver function (serum total bilirubin of less than 2 mg/dL); or
   5. 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, gallbladder cancer, and uveal melanoma, 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, liver metastases from colorectal cancer, and for primary and liver-dominant metastatic disease of the liver because of insufficient evidence in the peer-reviewed literature.

6. Electro-Chemotherapy

   Aetna considers electro-chemotherapy experimental and investigational for the treatment of liver malignancies because the effectiveness of this approach has not been established.

7. Immunotherapy

   Aetna considers immunotherapy with dendritic cells and/or cytokine-induced killer cells for the treatment of hepatocellular carcinoma experimental and investigational because the effectiveness of this approach has not been established.

8. Electro-Coagulation

   Aetna considers electro-coagulation experimental and investigational for the treatment of liver metastases because the effectiveness of this approach has not been established.

See also  CPB 0274 - Ablation of Hepatic Lesions.

Background

Chemo-embolization (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 hepato-cellular 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 chemo-embolization (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 computed tomography (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.  An 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. 

Selective Internal Radiation Therapy (SIRT), also known as radioembolization, is a procedure in which tiny radiation filled beads, called microspheres, are delivered directly to the tumor. The microspheres are delivered through a catheter placed in the femoral artery and threaded through the hepatic artery to the tumor site. The microspheres contain yttrium-90. Examples of this type of treatment include: SIR-Spheres, which are resin spheres that are indicated for the treatment of unresectable metastatic liver tumors from primary colorectal cancer; and Theraspheres, which are spheres made of glass, and are indicated for primary unresectable hepatocellular carcinoma (HCC). 

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 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): 

• Histologically confirmed non-resectable lesion confined to the liver and at least 1 measurable lesion; and
   
  • Absolute granulocyte count greater than or equal to 2.0 x 10 9/L
  • 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]
  • 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]
  • Estimated life expectancy greater than or equal to 12 weeks
  • 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);
  • Platelet count greater than or equal to 100 x 109/L
  • 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
  • Eastern Cooperative Oncology Group (ECOG) performance status score less than or equal to 3
     
• Adequate bone marrow and hepatic function; and 
• No contraindications to hepatic artery catheterization (e.g., vascular abnormalities, bleeding diathesis, allergy to contrast dye, or portal vein thrombosis); and 
• No other concurrently planned oncotherapy; and
• At least 1 month post other chemotherapy or surgery.

The following exclusion criteria apply:  

• Previous chemotherapy or radiation therapy for hepatoma; or 
• Potential absorbed dose to lungs greater than 30 Gy; or 
• Any uncorrectable angiographic flow to the gastrointestinal tract; or
• 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:

• Hepatic angiogram which entails placement of intra-hepatic catheter to assess vasculature and TheraSphere delivery route, and
• 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:

• Multiple liver metastases together with involvement of both lobes; or
• 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
• 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
• 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 magnetic resonance imaging (MRI).

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

• A hepatic angiogram should be performed to establish arterial anatomy of the liver;
• 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;
• 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.

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 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.

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”.

In a prospective, single-center, phase I study, Cohen et al (2014) documented the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and the recommended phase II dose for future study of capecitabine in combination with radio-embolization.  Patients with advanced unresectable liver-dominant cancer were enrolled in a 3+3 design with escalating doses of capecitabine (375 to 1,000 mg/m(2) b.i.d.) for 14 days every 21 days.  Radio-embolization with (90)Y-resin microspheres was administered using a sequential lobar approach with 2 cycles of capecitabine.  A total of 24 patients (17 colorectal) were enrolled.  The MTD was not reached.  Hematologic events were generally mild.  Common grade 1/2 non-hematologic toxicities included transient transaminitis/alkaline phosphatase elevation (9 (37.5 %) patients), nausea (9 (37.5 %)), abdominal pain (7 (29.0 %)), fatigue (7 (29.0 %)), and hand-foot syndrome or rash/desquamation (7 (29.0 %)).  One patient experienced a partial gastric antral perforation with a capecitabine dose of 750 mg/m(2).  The best response was PR in 4 (16.7 %) patients, SD in 17 (70.8 %) and progression in 3 (12.5 %).  Median time to progression and OS of the metastatic CRC cohort was 6.4 and 8.1 months, respectively.  The authors concluded that this combined modality treatment was generally well-tolerated with encouraging clinical activity.  Capecitabine 1,000 mg/m(2) b.i.d. is recommended for phase II study with sequential lobar radio-embolization.

An UpToDate review on “Management of locally advanced unresectable and inoperable esophageal cancer” (Heron and Gibson, 2014) and NCCN’s clinical practice guideline on “Esophageal and esophagogastric junction cancers” (Version 1.2015) do not mention chemoembolization as a therapeutic option.

Trans-Arterial Chemo-Embolization Plus Sorafenib

Li and colleagues (2018) noted that TACE is the recommended treatment for HCC patients at Barcelona Clinic Liver Cancer (BCLC) B-stage, whereas sorafenib is an orally administered small molecule target drug for BCLC C-stage.  This updated systemic review and meta-analysis focused on identifying the efficacy of the combination of TACE with sorafenib, which remains controversial despite years of exploration.  PubMed, Embase, Scopus and the Cochrane Library were systematically reviewed to search for studies published from January 1990 to May 2017.  Studies focusing on the efficacy of combination therapy for unresectable HCC were eligible.  The HR with 95 % CIs for TTP, OS, DCR and etiology were collected.  The data were then analyzed through fixed/random effects meta-analysis models with STATA 13.0.  The incidence and severity of treatment-related adverse events (AEs) were also evaluated.  A total of 27 studies were included; 13 non-comparative studies reported median OS (ranging from 18.5 to 20.4 months), median TTP (ranging from 7 to 13.9 months) and DCR (ranging from 18.4 to 95 %); 14 comparative studies provided median OS (ranging from 7.0 to 29.7 months) and median TTP (ranging from 2.6 to 10.2 months); 5 comparative studies provided DCR (ranging from 32 to 97.2 %).  Forest plots showed that combination therapy significantly improved TTP (HR = 0.66, 95 % CI: 0.50 to 0.81, p = 0.002) rather than OS (HR = 0.63, 95 % CI: 0.55 to 0.71, p = 0.058), compared to TACE alone.  DCR increased significantly in the combination therapy group (OR = 2.93, 95 % CI: 1.59 to 5.41, P = 0.005).  Additional forest plots were drawn and no significant differences were observed with regard to survival outcome among various etiologies.  Forest plots for separate analysis of regions showed the HR for TTP was 0.62 (95 % CI: 0.45 to 0.79, p = 0.002) in the Asian countries group, and 0.82 (95 % CI: 0.59 to 1.05, p = 0.504)) in Western countries.  The HR for OS was 0.61 (95 % CI: 0.48 to 0.75, p = 0.050) in the Asian countries group and was 0.88 (95 % CI: 0.56 to 1.20, p = 0.845) in Western countries.  These data may indicate positive TTP outcome in Asian patients but not in European patients while no positive findings regarding OS were observed in either region.  The most common AEs included fatigue, hand-foot skin reaction, diarrhea and hypertension.  The authors concluded that combination therapy may benefit unresectable HCC patients in terms of prolonged TTP and DCR; however, they stated that well-designed, randomized-controlled, prospective trials with optimized study designs and large sample sizes are needed.

The authors stated that this study had several drawbacks.  First, the number of studies included in this meta-analysis was relatively large, with 50 % being non-comparative -- the heterogeneity of available data from these studies was correspondingly substantial.  The funnel plots also showed potential publication bias.  Second, only several studies conducted OS and TTP analysis.  The detailed information available for meta-analysis was limited.  Third, the retrospective nature, small sample size, non-randomized study design and the various treatment procedures may increase the uncertainty of the conclusions.

Chauhan and associates (2018) stated that the objective of the TheraSphere in the Treatment of Patients with Unresectable Hepatocellular Carcinoma (STOP-HCC) Trial is to examine the hypothesis that trans-arterial radio-embolization (TARE; TheraSphere Y90 glass microspheres) combined with standard 1st-line treatment with sorafenib will improve outcomes over treatment with sorafenib alone in unresectable HCC.  The STOP-HCC study is the largest international, multi-center, prospective study of intra-arterial treatment in combination with sorafenib in unresectable HCC.  These researchers described the study design.  STOP-HCC is a prospective, randomized controlled , open-label, phase-III clinical trial that is conducted across up to 105 sites in North America, Europe, and Asia.  Eligible adults have unresectable HCC and a life expectancy of at least 12 weeks, 1 or more uni-dimensional measurable lesions, Child-Pugh score 7 points or less, and ECOG Performance Status score 1 or lower, and are candidates for treatment with sorafenib.  Presence of branch portal vein tumor thrombosis is permitted.  Patients were randomly assigned in a 1:1 ratio to receive either sorafenib alone or TARE followed by sorafenib within 2 to 6 weeks.  The primary outcome is OS.  Secondary outcomes are TTP, time to untreatable progression, time to symptomatic progression, tumor response, QOL, and AE occurrence.  The study is an adaptive trial, comprising a group-sequential design with 2 interim analyses with 520 patients, and an option to increase the sample size to 700 patients at the 2nd interim analysis.  The sample size of 520 patients allows for 417 deaths to give 80 % power to detect an increase in median OS from 10.7 months for the sorafenib group (based on the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol [SHARP] trial) to 14.2 months for the TARE + sorafenib group (HR 0.754) with 2-sided alpha of 0.05.  The increased sample size of 700 patients allows for 564 deaths to give 80 % power to detect a smaller difference in median OS from 10.7 months for the sorafenib group to 13.7 months for the TARE + sorafenib group (HR 0.781).  Enrollment for the study was completed in September 2017.  Results of the 1st and 2nd interim analyses were reviewed by the Independent Data Monitoring Committee.  The recommendation of the Committee, at both interim analyses, was to continue the study without any changes.  The authors concluded that the STOP-HCC Trial will contribute toward the establishment of the role of combination therapy with TARE and sorafenib in the treatment of unresectable HCC with and without branch portal vein tumor thrombosis.

Trans-Arterial Radio-Embolization (TARE) with TheraSphere Yttrium-90 Glass Microspheres Combined with Second-Line Therapy in Individuals with Metastatic Colorectal Cancer of the Liver

Chauhan and colleagues (2019) stated that CRC is one of the commonest cancers and causes of cancer-related death.  Up to 70 % of patients with mCRC have metastases to the liver at initial diagnosis.  Second-line systemic treatment in mCRC can prolong survival after development of disease progression during or after 1st-line treatment and in those who are intolerant to 1st-line treatment.  The objective of this study is to evaluate the safety and efficacy of TARE with TheraSphere 90Y glass microspheres combined with 2nd-line therapy in patients with mCRC of the liver who had disease progression during or after 1st-line chemotherapy.  EPOCH is an prospective, randomized, multi-center, open-label, phase-III clinical trial that is being conducted at up to 100 sites in the United States, Canada, Europe, and Asia.  Eligible patients have mCRC of the liver and disease progression after 1st-line chemotherapy with either an oxaliplatin-based or irinotecan-based regimen and are eligible for 2nd-line chemotherapy with the alternate regimen.  Patients were randomized 1:1 to the TARE group (chemotherapy with TARE in place of the 2nd chemotherapy infusion and subsequent resumption of chemotherapy) or the control group (chemotherapy alone).  The addition of targeted agents is permitted.  The primary end-points are progression-free survival (PFS) and hepatic PFS.  The study objective will be considered achieved if at least 1 primary end-point is statistically significant.  Secondary end-points are OS, time to symptomatic progression defined as ECOG Performance Status score of 2 or higher, objective response rate (ORR), DCR, QOL assessment by the Functional Assessment of Cancer Therapy-Colorectal Cancer questionnaire, and AEs.  The study is an adaptive trial, comprising a group sequential design with 2 interim analyses with a planned maximum of 420 patients.  The study is designed to detect a 2.5-month increase in median PFS, from 6 months in the control group to 8.5 months in the TARE group (HR 0.71), and a 3.5-month increase in median hepatic PFS time, from 6.5 months in the control group to 10 months in the TARE group (HR 0.65).  On the basis of simulations, the power to detect the target difference in either PFS or hepatic PFS is greater than 90 %, and the power to detect the target difference in each end point alone is greater than 80 %.  Patient enrollment ended in October 2018.  The first interim analysis in June 2018 resulted in continuation of the study without any changes.  The authors concluded that the EPOCH study may contribute toward the establishment of the role of combination therapy with TARE and oxaliplatin- or irinotecan-based chemotherapy in the 2nd-line treatment of mCRC of the liver.  These researchers stated that drawbacks of the study include the un-blinded design, which is needed for such a complex treatment intervention when it would be unethical to consider a sham procedure for the control group.

Drug-Eluting Beads for Hepatocellular Carcinoma

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.

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.

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.

Cannon et al (2012) assessed the safety and effectiveness of chemoembolization with doxorubicin-eluting beads (DEBDOX) in the treatment of multi-nodular (greater than or equal to 10 lesions) HCC.  A 503-patient prospective multi-national DC Bead registry database from 6/2007 to 2/2010 identified 176 patients treated for HCC with DEBDOX.  There were 42 patients with multi-nodular HCC compared to 134 with non-multinodular HCC.  After a median follow-up of 12 months, the multi-nodular group response rate according to modified RECIST criteria was 56 % and median overall survival was 7.6 months, compared to 57 % and 15 months in the non-multi-nodular group (p = 0.08).  The authors concluded that multi-nodular HCC represents a more advanced stage of disease; however, DEBDOX treatment is safe and effective when compared to historical controls and current best systemic therapy.  They stated that continued hepatic arterial therapy and evaluation is needed in this clinical subset to further confirm these results.

Lencioni et al (2013) stated that TACE is the current standard of care for patients with intermediate-stage HCC and relatively preserved liver function.  In a meta-analysis of RCTs comparing conventional TACE regimens including the administration of an anticancer-in-oil emulsion followed by embolic agents versus best supportive care, TACE was shown to improve median survival from 16 to 20 months.  Various strategies to improve outcomes for this patient group have become the subject of much ongoing clinical research.  The introduction of an embolic DEB has been shown to substantially improve the pharmacokinetic profile of TACE, providing levels of consistency and repeatability not available with conventional regimens while concomitantly significantly diminishing systemic drug exposure.  In randomized trials, DEB-TACE significantly reduced liver toxicity and drug-related adverse events compared with conventional TACE.  These investigators reviewed technique, indications and contraindications, and clinical outcomes of conventional and DEB-TACE in the management of HCC.  In addition, scientific background and early clinical experience with the use of combination regimens including TACE and systemically active molecular-targeted agents with anti-angiogenic properties were discussed.  The authors concluded that the combination of DEB-TACE and anti-angiogenic therapy represents a potentially powerful approach that is currently undergoing clinical investigation in a phase III setting.

Drug-eluting beads have been used during TACE therapy for the treatment of HCC (NIHR HSRIC, 2016). The majority of the blood supply to the normal liver parenchyma comes from the portal vein, whereas blood flow to the tumor typically comes mainly from the hepatic artery. Furthermore, HCC tumors are generally hypervascular compared with the surrounding normal parenchymaa. TACE involves the intra-arterial injection of polyvinyl alcohol beads or particles loaded with a chemotherapeutic agent, such as doxorubicin, around a tumor. The blood supply to the tumor is then reduced or ceases altogether, causing it to shrink or die. The reduced blood supply also allows the chemotherapeutic agent to remain at the site of the tumor longer, exposing the tumor cells to higher levels of the chemotherapeutic and reducing the peak systemic plasma levels (NIHR HSRIC, 2016).

In a meta-analysis, Gao and associates (2013) evaluated the effectiveness of DEB-TACE compared with conventional TACE (cTACE).  These researchers included 7 studies (a total of 693 patients) to compare DEB-TACE with cTACE.  The pooled (OR were calculated using a random or fixed effects model.  MEDLINE, EMBASE and the Cochrane Database were searched for articles published from dates of inceptions up to February 20, 2012.  Sensitivity analysis and publication bias estimate were also performed to evaluate the potential risk bias in the overall results of pooled analysis.  The pooled estimates for tumor response of DEB-TACE were not significantly different from those of cTACE, with CR (OR: 1.18; 95 % CI: 0.81 to 1.71; p = 0.394), PR (OR: 1.37; 95 % CI: 0.94 to 1.99; p = 0.101), stable disease (SD) (OR: 0.88; 95 % CI: 0.51 to 1.51; p = 0.637), progressive disease (PD) (OR: 0.85; 95 % CI: 0.52 to 1.38; p = 0.512), DC (OR: 1.37, 95 % CI: 0.95 to 1.98; p = 0.089) and OR (OR: 1.40; 95 % CI: 0.97 to 2.000; p = 0.070).  The authors concluded that the current evidence suggests that DEB-TACE is able to accomplish the same tumor response as cTACE.  Moreover, they stated that although this analysis provided a comprehensive look at published data involving the clinical effectiveness of DEB-TACE compared with conventional TACE, additional large scale of RCTs are still needed.

An UpToDate review on “Nonsurgical therapies for localized hepatocellular carcinoma: Transarterial embolization, radiotherapy, and radioembolization” (Curley et al, 2013) states that “A newer approach to TACE uses drug-eluting beads (DEBs) that slowly release chemotherapy, thus diminishing systemic toxicity.  Early results from retrospective reports and several small prospective randomized trials suggest similar rates of tumor control as with conventional TACE, with lower rates of serious hepatobiliary toxicity, although follow-up is short in most series:

• A meta-analysis of seven studies comparing conventional TACE versus DEB-TACE (five prospective randomized trials and two retrospective comparative reports, totaling 693 patients) concluded that the pooled estimates for tumor response with DEB-TACE were not significantly different from those of conventional TACE (odds ratio [OR] for disease control 1.37, 95 % CI 0.95-1.98).
• Comparative toxicity was addressed in the largest randomized trial, the PRECISION V trial, in which conventional TACE using doxorubicin (50 to 75 mg/m2) was directly compared to DEB-TACE (150 mg doxorubicin per procedure) in 212 patients with Child-Pugh A/B cirrhosis and unresectable HCC.  The DEB group had lower rates of treatment-emergent adverse events in the hepatobiliary system (16 versus 25 percent).  The mean maximum postchemoembolization alanine transaminase increase with DEB-TACE was 50 percent less than in the conventional TACE group (p < 0.001), and the mean maximum aspartate transaminase increase was 41 percent lower.  Furthermore, despite a higher mean total dose of doxorubicin in the DEB-TACE group (295 versus 233 mg), there was a small but statistically significant difference in mean change from baseline in left ventricular ejection fraction (LVEF) of 4 percentage points that favored DEB-TACE group.  The incidence of postembolization syndrome was similar between both groups (25 versus 26 percent for DEB-TACE and conventional TACE).  On the other hand, treatment-emergent gastrointestinal adverse events occurred more often in patients treated with DEB-TACE (61 versus 45 percent).

The authors noted that “Where available, TACE using drug-eluting beads may be preferred, although long-term experience with this modality is limited”.

Furthermore, the NCCN clinical practice guideline on “Hepatobiliary cancers” (Version 1.2013) notes that “Recent studies have evaluated TACE with drug-eluting beads in patients with unresectable HCC …. These results need to be confirmed in larger prospective studies”.

Idilman et al (2013) determined the effect of trans-arterial chemo-embolization (TACE) treatment on survival in patients with HCC and examined the efficacy and tolerability of 2 different TACE procedures:

1. Conventional TACE and
2. Drug-eluting beads (DEB), in these patients. 

A total of 40 patients with HCC treated with TACE between January 2007 and March 2011 were included.  Thirty-seven patients had Child-Pugh class A and the remaining 3 had class B.  Intra-arterial administration of doxorubicin with lipiodol-based conventional TACE or DEB-TACE was performed.  Eighty sessions were performed with a median of 2 sessions.  Sixteen patients were treated with conventional TACE and 11 with DEB-TACE, and 13 were treated with both treatment procedures in separate sessions.  Primary outcome was defined as patient survival after treatment.  The median follow-up was 19 months.  The median overall survival of patients was 23.2 months.  The survival of patients with Child-Pugh class A was significantly better than that of patients with class B (24 versus 6 months, p = 0.004).  No statistically significant difference in survival was observed between conventional TACE and DEB-TACE treatments (p > 0.05).  Baseline low serum albumin level (p = 0.003) and the presence of portal vein thrombosis (p = 0.011) negatively affected patient survival.  Side effects of conventional TACE and DEB-TACE were similar.  The authors concluded that based on the results of this study and in comparison with the findings in the literature, TACE treatment was seen to improve overall survival and provide better outcome in selected patients with HCC.  They stated that no differences in survival or side effects were observed between the 2 TACE treatment modalities (conventional TACE and DEB-TACE).

An UpToDate review on “Nonsurgical therapies for localized hepatocellular carcinoma: Transarterial embolization, radiotherapy, and radioembolization” (Curley et al, 2014) states that “Drug-eluting beads -- A newer approach to TACE uses drug-eluting beads (DEBs) that slowly release chemotherapy, thus diminishing systemic toxicity.  Early results from retrospective reports and several small prospective randomized trials suggest similar rates of tumor control as with conventional TACE, with lower rates of serious hepatobiliary toxicity, although follow-up is short in most series”.

Furthermore, the NCCN’s clinical practice guideline on “Hepatobiliary cancers” (Version 1.2015) notes that “DEB-TACE has also been evaluated in patients with unresectable HCC …. Malagari et al also showed that DEB-TACE resulted in higher response rates, lower recurrences, and longer TTP compared to TAE in patients with intermediate-state HHC; however, this study also did not show any OS benefit for DEB-TACE …. Dhanasekaran et al reported a survival advantage for DEB-TACE over conventional TACE in a prospective randomized study of 71 patients with unresectable HCC.  However, these results need to be confirmed in large propsective studies”.

Spreafico et al (2015) evaluated the short-term safety and effectiveness of the new generation of 70-150 µm drug-eluting beads (M1 DEB) in patients with hepatocellular carcinoma undergoing TACE as a primary therapy or as a bridge to liver transplantation (LT).  A total of 45 consecutive patients underwent TACE with M1 DEB loaded with doxorubicin (DEBDOX/M1).  Clinical data were recorded at 12, 24, and 48 hours, 7 and 30 days after treatment.  Response was assessed by computed tomographic scan according to the modified response evaluation criteria in solid tumors criteria, and a second DEBDOX/M1 TACE was scheduled within 6 weeks in case of a non-complete response.  All patients had well-compensated cirrhosis (97.7 % Child A, 44.4 % hepatitis C virus, median age of 61 years).  Twenty patients (44.4 %) had Barcelona Clinic for Liver Cancer class B disease; the median number of nodules and their sum of diameters were 2 (range of 1 to 6) and 43 mm (range of 10 to 190), respectively.  The mean number of TACE procedures per patient was 1.4.  Objective response rate (complete + partial response) was 77.7 % with a median time to best response of 3 months (95 % confidence interval [CI]: 2 to 4).  In 13 patients, DEBDOX/M1 TACE served as a bridge/down-staging to LT/surgery.  Pathology showed that more than 90 % necrosis was achieved in 10 of 28 nodules.  DEBDOX/M1 TACE was well-tolerated, and the grade 3/4 adverse event rate was low (1 of 65 procedures).  The authors concluded that DEBDOX/M1 TACE is an effective procedure with a favorable safety profile and promising results in terms of objective response rate, tumor down-staging, and necrosis.

Facciorusso et al (2016a) noted that solid demonstrations of superior effectiveness of DEB-TACE with respect to conventional chemoembolization in HCC patients are lacking.  These investigators compared these 2 techniques in 2 large cohorts of unresectable HCC patients.  A single Center series of 249 early/intermediate HCC patients who underwent "on demand" chemoembolization in the period 2007 to 2011 was analyzed.  Overall survival, time to progression, tumor response rate and safety were compared between 104 patients who underwent conventional chemoembolization and 145 who underwent DEB chemoembolization.  Time-to-event data were analyzed using the Cox univariate and multivariate regression.  The 2 cohorts resulted balanced for liver function and tumor stages.  Objective response rate was 85.3 % after conventional and 74.8 % after DEB chemoembolization (p = 0.039), and median time to progression was 17 [95 % CI: 14 to 21] versus 11 months (9 to 12), respectively (p < 0.001).  Treatment regimen was the sole independent predictor of progression at multivariate analysis [HR = 2.01; CI: 1.45 to 2.80; p < 0.001].  Median survival was 39 (32 to 47) and 32 (24 to 39) months in the 2 groups, respectively (HR = 1.33; CI: 0.94 to 1.87; p = 0.10) but conventional chemoembolization was significantly associated with a survival advantage in patients with bilobar neoplasia, portal hypertension and alpha-fetoprotein above normal limits.  No significant differences in severe adverse events were found.  The authors concluded that in a large series of Western HCC patients, DEB chemoembolization with 100 to 300 µm particles did not seem to improve survival in comparison to conventional chemoembolization, which in turn provided better tumor responses and time to progression.

Facciorusso et al (2016b) noted that despite the promising results of earlier studies, a clear superiority of DEB-TACE over cTACE in unresectable HCC patients has not been established yet.  These researchers evaluated the safety and  effectiveness of these 2 treatments in unresectable HCC patients.  They carried out computerized bibliographic search on the main databases; 1-year, 2-year, 3-year survival rates were analyzed; HR from Kaplan-Meier curves were extracted to perform an unbiased comparison of survival estimates.  Objective response and severe AE rate were analyzed too.  A total of 4 RCTs and 8 observational studies with 1,449 patients were included in the meta-analysis.  Non-significant trends in favor of DEB-TACE were observed as for 1-year (OR: 0.76, 95 % CI: 0.48 to 1.21, p = 0.25), 2-year (OR: 0.68, 95 % CI: 0.42 to 1.12, p = 0.13) and 3-year survival (OR: 0.57, 95 % CI: 0.32 to 1.01, p = 0.06).  Meta-analysis of plotted HRs confirmed this trend (HR: 0.86, 95 % CI: 0.71 to 1.03, p = 0.10).  Pooled data of objective response showed no significant difference between the 2 treatments (OR: 1.21, 95 % CI: 0.69 to 2.12, p = 0.51).  No statistically significant difference in AEs was registered (OR: 0.85, 95 % CI: 0.60 to 1.20, p = 0.36).  The authors concluded that these findings indicated a non-superiority of DEB-TACE with respect to cTACE in patients with HCC.

Baur and co-workers (2016) stated that in HCC patients with large or multi-nodal tumors, where curative treatment options are not feasible, trans-arterial therapies play a major role; DEB-TACE is a promising new approach due to higher intra-tumoral and lower systemic concentration of the chemotherapeutic agent compared to cTACE.  In a retrospective analysis, 32 patients with HCC who received either DEB-TACE or a cTACE were compared regarding survival time, disease recurrence, and AEs such as pain and fever.  No significant differences could be detected between the cTACE and DEB-TACE groups with regard to mean hospital stay, appearance of post-interventional fever, or 30-day mortality.  However, the application of intravenous analgesics as post-interventional pain medication was needed more often in patients treated with DEB-TACE (57.1 % versus 12.5 %, p = 0.0281).  The overall median survival after the initial procedure was 10.8 months in the cTACE group and 9.2 months in the DEB-TACE group, showing no significant difference.  The authors concluded that no survival benefit for patients treated with either DEB-TACE or cTACE was observed; however, a higher rate of post-interventional pain could be detected after DEB-TACE.

Rahman and associates (2016) compared survival rates and tumor response between patients undergoing cTACE and DEB-TACE at their center.  A retrospective cohort study of patients undergoing either treatment was carried out from January 2009 to December 2014.  Tumor response to the procedures was evaluated according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST).  Kaplan-Meier analysis was used to assess and compare the OS in the 2 groups.  A total of 79 patients were analyzed (34 had cTACE, 45 had DEB-TACE) with a median follow-up of 11.8 months.  A total of 20 patients in the cTACE group (80 %) and 12 patients in the DEB-TACE group (44 %) died during the follow-up period.  The median survival durations in the cTACE and DEB-TACE groups were 4.9 ± 3.2 months and 8.3 ± 2.0 months, respectively (p = 0.008).  There was no statistically significant difference noted between the 2 groups with respect to mRECIST criteria.  The authors concluded that DEB-TACE demonstrated a significant improvement in OS rates for patients with unresectable HCC when compared to cTACE.  They stated that DEB-TACE is a safe and promising approach and should potentially be considered as a standard of care in the management of unresectable HCC.

Massani and colleagues (2017) evaluated their experience in the treatment of intermediate/advanced HCC with cTACE versus DEB-TACE; OS was the first end-point.  These investigators retrospectively considered their department register data between 2006 and 2012.  A total of 82 non-surgical patients, who underwent cTACE or DEB-TACE, with a minimum of 12 months follow-up, met the inclusion criteria.  Patients received a standard chemotherapy dose (50 mg).  Radiological response was evaluated by CT after 30 days and re-treatment was considered.  Statistical analysis was performed with SPSS software.  A total of 54 patients received cTACE and 28 DEB-TACE.  In the DEB-TACE group the median survival times was 22.7 months (95 % CI: 11.6 to 33.8), while in the cTACE group it was 21.8 months (95 % CI: 15.7 to 27.9).  The survival analysis at log-rank (p = 0.708) and Wilcoxon (p = 0.661) tests demonstrated no differences between DEB-TACE and cTACE.  The probability of death in function of time was significantly associated only to the Child-Pugh score.  A Child A score was shown to be protective instead of Child B (OR 0.583; 95 %CI: 0.344 to 0.987); DEB-TACE for treating HCC was comparable to cTACE in terms of effectiveness, but appeared to be better tolerated.  Both treatments can be performed in case of tumor recurrence without substantial increase in procedural complications and risk of liver failure.  The authors confirmed that there were no differences between the 2 techniques in terms of survival and that it was mainly affected by the reserved liver function proper of each patient.

Drug-Eluting Beads for Liver Metastases from Colorectal Cancer

Drug-eluting beads have been used during TACE therapy for the treatment of unresectable, liver dominant/liver only metastatic colorectal cancer (NIHR HSRIC, 2016). This usually involves the intra-arterial injection of polyvinyl alcohol beads or particles and a chemotherapeutic agent, such as irinotecan, around a tumor. The blood supply to the tumor is then reduced or ceases altogether, causing it to shrink or die. The reduced blood supply also allows the chemotherapeutic agent to remain at the site of the tumor longer, exposing the tumor cells to higher levels of the chemotherapeutic agent and reducing the peak systemic plasma levels (NIHR HSRIC, 2016).

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 single-center, phase II clinical trial, Iezzi and colleagues (2015) evaluated the feasibility, tolerance, safety and effectiveness of drug-eluting beads loaded with irinotecan (DEBIRI) in combination with capecitabine in the treatment of metastatic colo-rectal cancer (mCRC) refractory to chemotherapy in patients affected by liver predominant metastatic disease.  A total of 20 patients affected by CRC hepatic metastasis with liver-dominant disease, who had progression after 2 or more lines of chemotherapy, were enrolled.  Transcatheter arterial chemo-embolization with 100 mg of irinotecan loaded into 2-ml of 70 to 150 µm DEB was administrated every 4 weeks in patients with unilobar disease (2 treatments) and every 2 weeks in patients with bilobar disease (4 treatments).   All patients assumed capecitabine 1,000 mg/m(2) twice-daily on days 1 to 14 every 3 weeks, until disease progression.  Primary end-points were safety, tolerance and overall disease control (ODC); secondary end-points were PFS and OS.  A total of 54 treatments were performed (54/66, 82 %).  No intra-/peri-procedural death occurred.  During the mean follow-up of 11 months, 2 PR were reported with ODC of 60 % (2 PR + 10 SD).  Progression free survival and OS were 4 and 7.3 months, respectively.  Univariate analysis showed that patients presenting with KRAS wild-type, good Eastern Cooperative Oncology Group (ECOG) performance status and unilobar disease had a better prognosis.  Only performance status (ECOG) correlated with OS in multivariate analysis (p = 0.03).  The authors concluded that DEBIRI with capecitabine appeared to be a safe, technically feasible and well-tolerated treatment in chemotherapy refractory liver prevalent colorectal metastases.  These findings need to be validated by well-designed studies.

Pernot et al (2015) designed a prospective phase II clinical trial testing TACE using DEBIRI with concomitant systemic FOLFOX regimen, the FFCD 1201 trial, in patients with liver limited mCRC.  A 48-year old patient was operated from an occlusive sigmoid adenocarcinoma.  Magnetic resonance imaging showed 6 bilobar liver metastasis.  The patient was considered as non-eligible for surgery initially.  Patient was included in the FFCD 1201 trial and received 5 cycles of FOLFOX and 2 sessions of DEBIRI, with a quite good tolerability.  Post-treatment evaluation showed a PR and sufficient tumor shrinkage to make liver metastasis resectable.  Right hepatectomy associated with wedge resection in the left liver was performed and pathological findings showed a complete pathological response (CPR).  The authors concluded that combination of DEBIRI with FOLFOX could increase tumor shrinkage leading to secondary resection of liver metastases from CRC.  This combination may also, as shown here for the first time in a patient with unresectable liver metastases, induce CPR of all liver metastases, known to be associated with better outcome.  The authors stated that this case also emphasized the difficulty to morphologically assess pathological response and the need for new tool to better select patients who should be resected.  They stated that further results of the FFCD 1201 trial will bring more information on this new combination therapy.

In a pilot study, Ranieri and associates (2016) evaluated the effectiveness of DEBIRI for liver metastases from colorectal cancer; secondary aims were to evaluate survival and toxicity.  A total of 25 patients with metastases in less than 50 % of the liver and without extra-hepatic involvement were enrolled.  Treatment response assessment was performed by multi-detector contrast enhancement CT (MDCT) with evaluation of the enhancement pattern of the target lesion and tumor response rates according to mRECIST (Version 1.1).  All AEs were recorded by the Cancer Therapy Evaluation Program Common Terminology Criteria for Adverse Events, Version 3.0.  Associations of tumor response and variables were calculated using the Chi-squared test; OS was calculated using the Kaplan-Meier method.  Comparisons were made using the log-rank test.  According to mRECIST, CR was observed in 21.8 % of patients, PR in 13 %, SD in 52.2 % and PD in 13 % of patients.  Response rate (RR = CR + PR) was 34.8 %.  No associations between treatment response and variables such as Dukes' classification, grading and Kras status were found (p > 0.05).  The median OS was 37 months (95 % CI: 13.881 to 60.119).  Cox regression model showed that neither site, Dukes' classification, grading, Kras status nor number of chemotherapy treatments pre-DEBIRI influenced the OS.  The log-rank test showed no statistically significant difference in OS among patients who underwent 1, 2 or 3 DEBIRI treatments (χ2 = 2.831, p = 0.09).  The main toxicities included post-embolization syndrome (PES), hyper-transaminasemia and fever.  The authors concluded that the favorable tumor response and the favorable toxicity profile made DEBIRI treatment a potential 3rd-line therapy.  Moreover, these researchers stated that these findings should be interpreted with caution due to the small number of enrolled patients related to the pilot nature of the study.  They stated that further larger studies are needed to confirm these preliminary data to consider DEBIRI as an emerging attractive treatment in these patients.

In a retrospective analysis, Gorodetski and colleagues (2017) compared the overall survival in patients with HCC and portal venous thrombosis (PVT), treated with either cTACE or DEB-TACE.  This study included a total of 133 patients, treated without cross-over and compared head-to-head by means or propensity score weighting.  Mortality was compared using survival analysis upon propensity score weighting.  Adverse events and liver toxicity grade greater than or equal to 3 were recorded and reported for each TACE.  In order to compare with historical sorafenib studies, a sub-group analysis was performed and included patients who fulfilled the SHARP inclusion criteria.  The median overall survival (MOS) of the entire cohort was 4.53 months (95 % CI: 3.63 to 6.03); MOS was similar across treatment arms, no significant difference between cTACE (n = 95) and DEB-TACE (n = 38) was observed (MOS of 5.0 versus 3.33 months, respectively; p = 0.157).  The most common adverse events after cTACE and DEB- TACE, respectively, were as follows: post-embolization syndrome [n = 57 (30.0 %) and n = 38 (61.3 %)], diarrhea [n = 3 (1.6 %) and n = 3 (4.8 %)], and encephalopathy [n = 11 (5.8 %) and n = 2 (3.2 %)].  The authors concluded that this retrospective study could not reveal a difference in toxicity and efficiency between cTACE and DEB-TACE for treatment of advance staged HCC with PVT.  Further, subgroup analysis suggested that catheter-based intra-arterial therapies with TACE can be seen as an alternative for systemic therapy with sorafenib in selected patient cohorts with PVT.  Overall, only prospective randomized trials that would include a head-to-head comparison between TACE and sorafenib will finally solve the clinical dilemma of choosing the proper therapy in this subset of patients.

In a retrospective study, Monier and associates (2017) compared TACE-related hepatic toxicities of cTACE and DEB-TACE in patients with intermediate-stage HCC.  A total of 151 consecutive patients undergoing cTACE or DEB-TACE and MRI 3to 6 weeks before and after therapy were included.  Toxicity was assessed on imaging (global hepatic damages (GHD), overall biliary injuries, biliary cast, bile duct dilatation, intra-hepatic biloma, portal thrombosis), and clinico-biological follow-ups.  Tumor response, TTP, and OS were assessed.  Factors influencing complication rate were identified by generalized equation logistic regression model.  Biliary injuries and intra-hepatic biloma incidence were significantly higher following DEB-TACE (p < 0.001); DEB-TACE showed a significant increased risk of GHD (OR: 3.13 [1.74 to 5.63], p < 0.001) and biliary injuries (OR: 4.53 [2.37 to 8.67], p < 0.001).  A significant relationship was found between baseline prothrombin value and GHD, biliary injuries and intra-hepatic biloma (all p < 0.01), and between the dose of chemotherapy and intra-hepatic biloma (p = 0.001).  Only TTP was significantly shorter following DEB-TACE compared to cTACE (p = 0.025).  The authors concluded that DEB-TACE was associated with increased hepatic toxicities compared to cTACE; GHD, biliary injuries, and intra-hepatic biloma were more frequently observed with high baseline prothrombin value, suggesting that cTACE might be more appropriate than DEB-TACE in patients with less advanced cirrhosis.

Song and Kim (2017) noted that TACE is the current standard of therapy for patients with intermediate-stage (HCC according to the Barcelona Clinic Liver Cancer classification.  The concept of cTACE is the selective obstruction of tumor-feeding artery by injection of chemotherapeutic agents, leading to ischemic necrosis of the target tumor via cytotoxic and ischemic effects; DEBs have been imposed as novel drug-delivering agents for TACE, which allows for higher concentrations of drugs within the target tumor and lower systemic concentrations compared with cTACE.  The authors stated that in comparison with cTACE, DEB-TACE facilitates higher concentrations of drugs within the target tumor and lower systemic concentrations.  Despite the theoretical advantages of DEB-TACE, it is still controversial in several clinical studies as to whether DEB-TACE is superior to cTACE in terms of efficacy.  However, it appeared that DEB-TACE showed at least similar clinical outcomes and less adverse events than cTACE.  These investigators stated that in order to gain better results for these treatment modalities, selecting proper candidate patients for DEB-TACE or cTACE is needed; moreover, further well-defined studies are needed to identify combination strategies and to develop better treatment approaches for patients with advanced HCC.

Lee and co-workers (2017) evaluated clinical outcomes of patients with HCC who underwent DEB-TACE.  This study retrospectively compared the clinical outcomes of 250 consecutive patients who underwent DEB-TACE (n = 106) or cTACE (n = 144) in a tertiary center between January 2010 and April 2014.  The median age of the patients was 62 years and 81.6 % were men.  The primary end-point was OS. The TTP, radiological response rate using modified response evaluation criteria in solid tumors criteria at 1 month after treatment, and complication rates within 1 month were also compared.  The most common etiology was hepatitis B virus infection.  The median index tumor size was 2.8 cm, and 150 (60.0 %) patients had Barcelona Clinic Liver Cancer stage B.  Median TTP in the cTACE group was longer than in the DEB-TACE group (13.3 versus 10.8 months; p = 0.023).  However, DEB-TACE and cTACE groups showed no significant differences for mean OS (46.6 versus 44.9 months; p = 0.660) and disease control rate at 1 month (78.3 % versus 86.8 %; p = 0.076).  The OS, TTP, and disease control rate were also not different between 2 groups, even when sub-grouped by index tumor size.  The complication rates within 1 month were higher in the cTACE group (6.6 % versus 14.6 %; p = 0.048).  The authors concluded that DEB-TACE appeared to be a safe intra-arterial therapy.  However, it is not superior to cTACE in terms of efficacy.  Tumor size might not be a criterion to select treatment modality between cTACE and DEB-TACE in terms of efficacy.

Intra-Hepatic Microspheres for the Treatment of Cholangiocarcinoma

Wang et al (2017) noted that HCC and intra-hepatic cholangiocarcinoma (ICC) often present at stages where patients have limited therapeutic options.  Use of SIRT with yttrium-90 (Y-90) resin microspheres has progressed as data increasingly speak to its utility in patients with both intermediate and late stage disease in these cancers.  In anticipation of the pending completion of several prospective randomized controlled multi-center studies exploring the use of Y-90 resin microspheres in primary liver cancers, this article outlined mechanisms involved in SIRT administration and reviewed key safety and efficacy data that are currently available in the literature involving use of this therapy in both HCC and ICC.  The authors concluded that interventional oncology procedures, including SIRT, have become an essential part of the multi-disciplinary approach to management of liver cancer at most major medical centers.  Trans-arterial Y-90 radio-embolization is a promising treatment modality increasingly being used to treat various liver malignancies including HCC and ICC.  The clinical data in support of its use has continued to grow over the past decade.  This minimally invasive approach is primarily performed in the out-patient setting, which minimizes hospital stay and costs.  With proper patient selection which includes patient ECOG performance status not higher than 2 and well-preserved liver function with serum total bilirubin of less than 2 mg/dL, SIRT procedures boast benefits that outweigh the risks, with increased survival and disease control rates (DCRs), and maintenance of good quality-of-life (QOL) for patients with an unfortunate prognosis.  Side effects are few and include fatigue, abdominal pain, nausea and vomiting.  Grade 3 to 4 adverse events (AEs) such as gastro-intestinal (GI) ulcerations and radio-embolization-induced liver disease (REILD) are uncommon.  As the body of research with prospective, randomized, controlled multi-center studies with a focus on SIRT oncology procedures continues to grow, a more promising future exists for improved outcomes and survival for patients who have liver cancer with advanced disease and limited therapeutic options.

Jia et al (2017) evaluated the value of resin-based yttrium-90 (90Y) radio-embolization for unresectable and failed 1st-line chemotherapy (cisplatin plus gemcitabine) ICC.  From February 2006 to September 2015, a retrospective study was conducted of all patients who underwent resin-based 90Y therapy for unresectable and failed 1st-line chemotherapy ICC.  Tumor response was assessed using modified RECIST criteria; side effects were assessed using Common Terminology Criteria for Adverse Events version 4.03; survivals were calculated from the date of diagnosis of ICC, beginning of 1st-line chemotherapy and first 90Y procedure, respectively; effects of factors on survival were analyzed by Cox regression model.  A total of 24 patients (8 male and 16 female) were included in this study.  Mean 5.6 ± 1.6 cycles of 1st-line chemotherapy were performed prior to 90Y treatment.  The mean delivered activity of 90Y was 1.6 ± 0.4 GBq with a total of 27 treatments.  Disease control rate was 81.8 % at 3 months after 90Y therapy, with PR (n = 8, 36.4 %), SD (n = 10, 45.5 %) and PD (n = 6, 18.2 %).  CA199 changes pre- and 1 month post-treatment were complete (n = 2), partial (n = 2), none (n = 5) and progression (n = 2), respectively.  Side effects included fatigue (n = 21, 87.5 %), anorexia (n = 19, 79.2 %), nausea (n = 15, 62.5 %), abdominal pain (n = 10, 58.3 %), vomiting (n = 4, 16.7 %) and fever (n = 3, 12.5 %).  Radiation-induced GI ulcer was identified in 1 patient.  The mean follow-up was 11.3 ± 6.6 months, and the median survivals from the time of diagnosis of ICC, beginning of 1st-line chemotherapy and first 90Y procedure were 24.0, 16.0 and 9.0 months, respectively, and the 6-, 12-, 18-, 24- and 30-month survival after 90Y therapy were 69.9, 32.6, 27.2, 20.4 and 20.4 %, respectively.  ECOG performance status (p = 0.002) and lymph node metastases (p = 0.019) had statistically significant influence on OS.  The authors concluded that resin-based 90Y radio-embolization can provide palliative control of unresectable and failed first-line chemotherapy ICC in a salvage setting with acceptable side effects.

Filippi et al (2018) stated that ICC is a severe and rapidly progressive hepatic tumor.  Surgery is often impracticable due to locally advanced presentation.  On the other hand, chemotherapy has demonstrated only limited effectiveness.  For these reasons, liver-directed therapies have been successfully applied for treating ICC.  In particular, radio-embolization with Yttrium-90 (90Y)-labeled spheres has been reported to be a promising therapeutic approach for this neoplasia.  Two commercial forms of 90Y-labeled spheres are available: glass (TheraSphere) and resin (SIR-Spheres) microspheres.  These investigators reviewed the existing literature on the use of the resin microspheres for the treatment of unresectable and chemo-refractory ICC, focusing on the methodology, clinical applications and side effects.

Nezami et al (2018) noted that there are 2 different types of 90Y microspheres, glass and resin, in the market for 90Y radio-embolization (90Y-RE).  These investigators examined the dose of radiation delivered through glass versus resin-based 90Y-RE to ICC.  In this retrospective study, 10 patients with ICC underwent 90Y-RE, 5 underwent glass (Glass group) and other 5 resin (Resin group) microspheres.  Technetium-99m macro-aggregated albumin (Tc-99m MAA) shunt study was performed 2 weeks before 90Y-RE.  Within 2 hours from 90Y-RE, Bremsstrahlung SPECT/CT was obtained.  Regions of interest (ROIs) were segmented around the targeted tumor and the liver.  Tumor and liver volumes, corresponding radioactive counts, and tumor to liver count ratio were calculated using MIM software and compared between Glass and Resin groups.  Mean hepato-pulmonary shunt fraction was 7.1 versus 6.2 % for the Glass and Resin groups (p = 0.83), with no extrahepatic activity.  There was no difference in the activity and tumor uptake of administered Tc-99m MAA between both groups (p = 0.71 and p = 0.63).  Mean administered activity of 90Y in the Glass group was higher than the Resin group (73.2 ± 24.3 versus 44.5 ± 18.2 mCi, p < 0.001).  The tumor 90Y uptake was significantly higher in the Glass group compared to the Resin group (41.3 % versus 33.5 %, p < 0.001), corresponding to the mean tumor dose of 205.7 ± 19.7 versus 128.9 ± 10.6 Gy, respectively (p < 0.001).  The tumor to normal liver parenchyma 90Y dose ratio was significantly higher in the Glass group compared to the Resin group, 4.9 ± 0.7 versus 2.4 ± 0.3 respectably (p < 0.001).  The authors concluded that both 90Y glass and resin-based microsphere 90Y-RE are safe and feasible in patients with ICC, while 90Y glass microsphere delivers higher dose of 90Y to the targeted tumors.

An UpToDate review on “Treatment of localized cholangiocarcinoma: Adjuvant and neoadjuvant therapy and prognosis” (Anderson and Stuart, 2018) states that “Hepatic artery-based therapies, particularly radioembolization, appear promising for patients with locally advanced unresectable intrahepatic cholangiocarcinoma.  However, there is insufficient evidence to consider the use of any of these techniques after complete resection of an intrahepatic cholangiocarcinoma, except in the context of a clinical trial … There are no published data on use of radioembolization on the adjuvant setting”.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Hepatobiliary cancer” (Version 1.2018) states that “Other smaller series have also reported favorable response rates and survival benefit for patients with unresectable intrahepatic cholangiocarcinoma treated with TARE with yttrium-90 microspheres.  Due to the rarity of this disease, none of the these locoregional approaches has been evaluated in randomized clinical trials.  Nevertheless, based on the available evidence as discussed above, the panel has included locoregional therapy (category 2B) as an option for patients with unresectable or metastatic disease”.

Electro-Chemotherapy for the Treatment of Liver Malignancies

Electrochemotherapy is a combined use of certain chemotherapeutic drugs and electric pulses applied to the treated tumor nodule (Sersa and Miklavcic, 2008). Local application of electric pulses to the tumor increases drug delivery into cells, specifically at the site of electric pulse application.

Campana and colleagues (2019) noted that the treatment of tumors with electro-chemotherapy (ECT) has surged over the last 10 years.  Thanks to the transient cell membrane permeabilization induced by the short electric pulses used by ECT, cancer cells are exposed to otherwise poorly permeant chemotherapy agents, with consequent increased cytotoxicity.  The codification of the procedure in 2006 led to a broad diffusion of the procedure, mainly in Europe, and since then, the progressive clinical experience, together with the emerging technologies, have extended the range of its application.  These investigators reviewed the key advances in the ECT field since the European Standard Operating Procedures on ECT (ESOPE) 2006 guidelines and discussed the emerging clinical data on the new ECT indications.  First, technical developments have improved ECT equipment, with custom electrode probes and dedicated tools supporting individual treatment planning in anatomically challenging tumors.  Second, the feasibility and short-term efficacy of ECT has been established in deep-seated tumors, including bone metastases, liver malignancies, and pancreatic and prostate cancers (long-needle variable electrode geometry ECT), and GI tumors (endoscopic ECT).  Moreover, pioneering studies indicated lung and brain tumors as suitable future targets.  A further advance relates to new combination strategies with immunotherapy, gene electro-transfer (GET), calcium electroporation (EP), and radiotherapy.  Finally and fourth, cross-institutional collaborative groups have been established to refine procedural guidelines, promote clinical research, and explore new indications.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Hepatobiliary cancers” (Version 1.2019) does not mention does not mention electro-chemotherapy as a therapeutic option.

Hepatic Arterial Therapy With Oxaliplatin Plus Systemic Capecitabine for Liver Metastases from Breast Cancer

Lindgaard and colleagues (2018) stated that hepatic arterial treatment (HAT) for the treatment of liver metastases in patients with metastatic breast cancer (MBC) has only been examined in few studies.  Two phase-II clinical trials were initiated simultaneously to evaluate capecitabine in combination with oxaliplatin in patients with MBC and liver metastases.  These 2 trials were reported together.  Continuous capecitabine (1,300 mg/m2) was combined with oxaliplatin (85 mg/m2) alternating between systemic treatment and HAT followed by degradable starch microspheres with EmboCept® S every 2nd week; 4 patients participated in a pharmacokinetic analysis of oxaliplatin.  Each patient had samples taken when receiving oxaliplatin systemically and as HAT with and without EmboCept® S.  A total of 52 patients received HAT: 14 with liver metastases only and 38 patients with additional limited metastatic disease.  The patients had previously received a median of 2 (range of 0 to 6) chemo-therapeutic regimens for MBC.  The response rate was 42.3 % (95 % CI: 28.7 to 56.8 %) with 7.7 % CR and 34.6 % PR.  Median PFS was 10.8 months (95 % CI: 6.9 to 14.7 months) and median OS 27.6 months (95 % CI: 20.4 to 34.8 months).  The toxicity was moderate with hand-foot syndrome (15.4 %), neuropathy (9.6 %), fatigue (9.6 %), and abdominal pain (9.6 %) being the most common grade-3 AEs.  There was no clear difference between systemic blood concentrations of oxaliplatin when given systemic or as HAT.  The authors concluded that HAT oxaliplatin in combination with capecitabine was safe and efficient in patients with MBC.  These researchers stated that these findings were promising with high response rates and a long median PFS and OS.  These findings need to be further investigated in phase-III clinical trials.

Microbubble Contrast Agent (SonoVue) and Transcatheter Arterial Chemo-Embolization

Huang and colleagues (2019) compared the safety and efficacy of microbubble contrast agent (SonoVue) and TACE in combination with high-intensity focused ultrasound (HIFU) for treatment of patients with HCC.  Per inclusion criteria, these researchers retrospectively reviewed 52 patients with HCCs, and divided them into SonoVue group and TACE group.  Tumors were examined by enhanced MRI.  Change of lesions, alpha-feto-protein (APF) values, hepatic and renal function were measured pre- and post-operatively; AEs were observed and clinical follow-up was performed.  Clinical efficacy and the majority of treatment parameters were similar, except for time and energy required for the 1st massive grey-scale changes in SonoVue group, which were significantly lower than those in TACE group (p < 0.05).  For AEs, only rate of fever (3.85 %) in SonoVue group was significantly lower than that in TACE group (50.00 %, p < 0.05).  The “diagnosis and treatment cycle” in SonoVue group (11.5 ± 2.9) was remarkably shorter than TACE group (22.7 ± 6.3, p < 0.05).  Energy efficiency factor was positively correlated with distance from the deepest layer of lesion to the hepatic capsule or to the abdominal wall in SonoVue group, while that was negatively correlated with iodized oil deposition in TACE group.  The authors concluded that using microbubble (SonoVue) in HIFU procedure had a similar therapeutic effect compared with TACE, and did not increase the risk of treatment; it might present a new strategy in clinical treatment, especially for patients with a smaller diameter of HCC.

The authors stated that it should be noted that this study was a retrospective, non-randomized analysis, and was limited by the small sample size, in which only 26 patients were assigned to each group.  Secondly, the AFP value was checked within a month after HIFU treatment, which may not reach the period of AFP decline, thus, the AFP values for some patients have not significantly decreased as expected.  Finally, the longest duration of follow-up was only 33 months, and no data regarding more long-term follow-up was provided.  These researchers suggested that more cases and prospective RCTs are needed to verify these findings.

Immunotherapy with Dendritic Cells and Cytokine-induced Killer Cells for the Treatment of Hepatocellular Carcinoma

Chen and associates (2018) stated that dendritic cell (DC)-based immunotherapy has recently been reported frequently in the treatment of HCC; however, its efficacy remains controversial.  In a systematic review and meta-analysis, these researchers examined the clinical efficacy of DC-based immunotherapy on HCC.  PubMed, Cochrane Library, Embase and Web of Science were searched to identify clinical trials on DC-based immunotherapy for HCC published up to January 31, 2018.  The articles were selected according to pre-established inclusion criteria and methodologic quality, and publication bias were evaluated.  A total of 1,276 cases from 19 clinical trials were included.  Compared with traditional treatment, further DC-based therapy enhanced the CD4+ T/CD8+ T ratio (standardized mean difference [SMD]: 0.68, 95 % CI: 0.46 to 0.89, p < 0.001); increased the 1-year, 18-month and 5-year PFS rate and the 1-year, 18-month and 2-year OS rate (RR > 1, p < 0.05), prolonged the median PFS time (median survival ratio [MSR]: 1.98, 95 % CI: 1.60 to 2.46, p < 0.001) and median OS time (MSR: 1.72, 95 % CI: 1.51 to 1.96, p < 0.001); adverse reactions were mild.  The authors concluded that DC-based therapy not only enhanced anti-tumor immunity, improved the survival rate and prolonged the survival time of HCC patients, but it was also safe.  These researchers stated that these findings will provide encouraging information for further development of DC-based immunotherapy as an adjuvant treatment for HCC.  However, these findings must be interpreted with caution because of the small study numbers, publication bias and the various of study designs, pre-treatment and therapeutic processes of DCs.

Cao and colleagues (2019) noted that HCC has been revealed as the 2nd most common cause of cancer-related deaths worldwide.  The introduction of cell-based immunotherapy, including DCs and cytokine-induced killer cells (CIKs), has brought HCC patients an effective benefit.  However, the efficacy and necessity of cellular immunotherapy after different interventional therapy remains to be further explored.  These investigators examined the efficacy of cellular immunotherapy, involving DCs and CIKs, combined with different conventional treatments of HCC.  They carried out a literature search on PubMed and Web of Science up to February 15, 2019.  Long-term efficacy (OS and recurrence) and short-term adverse effects were examined to evaluate the effectiveness of immunotherapy with DCs and/or CIKs.  Review Manager 5.3 was used to perform the analysis.  A total of 22 studies involving 3,756 patients selected by eligibility inclusion criteria were forwarded for meta-analysis.  Combined with the conventional clinical treatment, immunotherapy with DCs and/or CIKs was shown to significantly improve OS at 6 months [RR = 1.07; 95 % CI: 1.01 to 1.13, p = 0.02], 1 year (RR = 1.12; 95 % CI: 1.07 to 1.17, p < 0.00001), 3 years (RR = 1.23; 95 % CI: 1.15 to 1.31, p < 0.00001) and 5 years (RR = 1.26; 95 % CI: 1.15 to 1.37, p < 0.00001).  Recurrence rate was significantly reduced by cellular immunotherapy at 6 months (RR = 0.50; 95 % CI: 0.36 to 0.69, p < 0.0001) and 1 year (RR = 0.82; 95 % CI: 0.75 to 0.89, p < 0.00001).  Adverse effect assessment addressed that immunotherapy with DCs and/or CIKs was accepted as a safe, feasible treatment.  The authors concluded that combination immunotherapy with DCs, CIKs and DC/CIK with various routine treatments for HCC was evidently suggested to improve patients' prognosis by increasing OS and reducing cancer recurrence.  Moreover, these researchers stated that further assessment of the efficacy of novel immune checkpoint inhibitors based on clinical trials will aid to better identify immunotherapy strategies to treat HCC.

The authors stated that this systematic review and meta-analysis had 2 main drawbacks.  First, although these investigators included 22 trials in the analysis, the DC and DC/CIK groups comprised only 5 and 4 trials, respectively.  Most of the trials were conducted in East Asian countries (China, Japan and South Korea); hence, they had less-sufficient statistical power due to the lack of multi-national or multi-racial clinical data.  Second, heterogeneity was observed between the included studies.  Factors, including stage of malignancy, different surgical method, number of immunotherapy fusion cycles, and duration of immunotherapy in different clinical centers could have contributed to the heterogeneity.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Hepatobiliary cancers” (Version 4.2019) stated that “Immunotherapy, or using immune system to treat cancer, is beginning to be investigated as adjuvant HCC treatment … Data are currently too preliminary for the panel to provide specific recommendations regarding immunotherapy treatment in an adjuvant setting”.

Intra-Hepatic Microspheres for the Treatment of Liver Metastases from Uveal Melanoma

Kennedy and Salem (2010) stated that radioembolization using radioactive yttrium-90-labeled microspheres is gaining a stronger foothold in the management of primary and metastatic hepatic cancers.  The expanding literature reveals good and encouraging results in both retrospective and prospective reports as demonstrated by low acute or late toxicity and high response rates.  This treatment modality, which is most beneficial in patients with good liver reserve and low Eastern Cooperative Oncology Group (ECOG) performance status, has led to improved time to liver progression and extended overall survival (OS).  Although phase-III clinical trials of radioembolization are ongoing as a first-line treatment of patients with metastatic colorectal cancer, there are sufficient phase-II and retrospective clinical data supporting its use in salvage therapy for most patients.  Patients with hepatocellular cancer, neuroendocrine tumors, and other primary sites, including breast and lung, have also shown promising response and survival increases in multi-institutional experiences.

An UpToDate review on “Management of metastatic uveal melanoma” (Carvajal, 2019) does not mention the use of intra-hepatic microspheres as a therapeutic option.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Uveal melanoma” (Version 1.2019) stated that “Selective internal radiation therapy for patients with liver metastases using 90-Yttrium has been reported in retrospective studies.  Further study is required to determine the appropriate patients for and risks and benefits of this approach”.

Electro-Coagulation for Liver Metastases

Storman and colleagues (2021) stated that primary liver tumors and liver metastases from CRC are two of the most common malignant tumors to affect the liver.  The liver is second only to the lymph nodes as the most common site for metastatic disease.  More than 50% of patients with metastatic liver disease will die from metastatic complications.  Electro-coagulation by diathermy is a method used to destroy tumor tissue, using a high-frequency electric current generating high temperatures, applied locally with an electrode (needle, blade, or ball).  The aim of this approach is to destroy the tumor completely, if possible, in a single session.  With the time, electrocoagulation by diathermy has been replaced by other techniques, but the evidence is unclear.  In a Cochrane review, these researchers examined the beneficial and harmful effects of electro-coagulation by diathermy, administered alone or with another intervention, versus no intervention, other ablation methods, or systemic treatments in patients with liver metastases.  They searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, Medline Ovid, Embase Ovid, LILACS, Science Citation Index Expanded, Conference Proceedings Citation Index - Science, CINAHL, ClinicalTrials.gov, ICTRP, and FDA to October 2020.  These investigators considered all randomized trials that evaluated beneficial and harmful effects of electro-coagulation by diathermy, administered alone or with another intervention, versus comparators, in patients with liver metastases, regardless of the location of the primary tumor.  They used standard methodological procedures expected by Cochrane; and examined risk of bias of the included trial using pre-defined risk of bias domains; and presented the review results incorporating the certainty of the evidence using GRADE.  These researchers included 1 randomized clinical trial with 306 participants (175 males; 131 females) who had undergone resection of the sigmoid colon, and who had 5 or more visible and palpable hepatic metastases.  The diagnosis was confirmed by histological assessment (biopsy) and by carcinoembryonic antigen (CEA) level.  The trial was conducted in Iraq.  The age of participants ranged between 38 and 79 years; and subjects were randomized to 4 different study groups.  The liver metastases were biopsied and treated (only once) in 3 of the groups: 75 received electro-coagulation by diathermy alone, 76 received electro-coagulation plus allopurinol, 78 received electro-coagulation plus dimethyl sulphoxide.  In the 4rth intervention group, 77 subjects functioning as controls received a vehicle solution of allopurinol 5-ml 4 x a day by mouth; the metastases were left untouched.  The status of the liver and lungs was followed by ultrasound (US) investigations, without the use of a contrast agent.  Participants were followed for 5 years.  The analyses were based on per-protocol data only analyzing 223 participants.  These investigators judged the trial to be at high risk of bias.  After excluding “non-evaluable patients”, the groups appeared comparable for baseline characteristics.  Mortality due to disease spread at 5-year follow-up was 98 % in the electro-coagulation group (57/58 evaluable patients); 87 % in the electro-coagulation plus allopurinol group (46/53 evaluable patients); 86 % in the electro-coagulation plus dimethyl sulphoxide group (49/57 evaluable patients); and 100 % in the control group (55/55 evaluable patients).  These investigators observed no difference in mortality between the electrocoagulation alone group versus the control group (RR 0.98, 95 % CI: 0.94 to 1.03; 113 participants; very low-certainty evidence).  They observed lower mortality in the electro-coagulation combined with allopurinol or dimethyl sulphoxide group versus the control group (RR 0.87, 95 % CI: 0.80 to 0.95; 165 participants; low-certainty evidence).  These researchers were very uncertain regarding post-operative deaths between the electro-coagulation alone group versus the control group (RR 1.03, 95 % CI: 0.07 to 16.12; 152 participants; very low-certainty evidence) and between the electro-coagulation combined with allopurinol or dimethyl sulphoxide groups versus the control group (RR 1.00, 95 % CI: 0.09 to 10.86; 231 participants; very low-certainty evidence).  The trial authors did not report data on number of participants with other AEs and complications, recurrence of liver metastases, time to progression of liver metastases, tumor response measures, and health-related QOL.  Data on failure to clear liver metastases were not provided for the control group.  The authors concluded that the evidence on the beneficial and harmful effects of electro-coagulation alone or in combination with allopurinol or dimethyl sulphoxide in patients with liver metastases was insufficient, as it is based on 1 randomized clinical trial at low-to-very low certainty.  It was very uncertain if there was a difference in all-cause mortality and post-operative mortality between electro-coagulation alone versus control.  It was also uncertain if electro-coagulation in combination with allopurinol or dimethyl sulphoxide may result in a slight reduction of all-cause mortality in comparison with a vehicle solution of allopurinol (control).  It was very uncertain if there is a difference in post-operative mortality between the electro-coagulation combined with allopurinol or dimethyl sulphoxide group versus control.  Data on other AEs and complications, failure to clear liver metastases or recurrence of liver metastases, time to progression of liver metastases, tumor response measures, and health-related QOL were most lacking or insufficiently reported for analysis.  Electro-coagulation by diathermy is no longer used in the described way, and this may explain the lack of further trials.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
CPT codes covered if selection criteria are met:
36245	Placement, arterial system; each first order abdominal, pelvic, or lower extremity artery branch, within a vascular family
36260	Insertion of implantable intra-arterial infusion pump (e.g., for chemotherapy of liver)
37242	Vascular embolization or occlusion, inclusive of all radiological supervision and interpretation, intraprocedural roadmapping, and imaging guidance necessary to complete the intervention; arterial, other than hemorrhage or tumor (eg, congenital or acquired arterial malformations, arteriovenous malformations, arteriovenous fistulas, aneurysms, pseudoaneurysms)
37243	for tumors, organ ischemia, or infarction
75894	Transcatheter therapy, embolization, any method, radiological supervision and interpretation
77750	Infusion or instillation of radioelement solution (includes three months of follow-up care)
77778	Interstitial radiation source application, complex, includes supervision, handling, loading of radiation source, when performed
96446	Chemotherapy administration into peritoneal cavity via indwelling port or catheter
CPT codes not covered for indications listed in the CPB:
Electro-chemotherapy, immunotherapy with dendritic cells and/or cytokine-induced killer cells, electro-coagulation - no specific code :
79445	immunotherapy with dendritic cells and/or cytokine-induced killer cells
Other CPT codes related to the CPB:
96420	Chemotherapy administration, intra-arterial; push technique [not covered for liver metastases from breast cancer]
96422	Chemotherapy administration, intra-arterial; infusion technique, up to 1 hour [not covered for liver metastases from breast cancer]
96423	Chemotherapy administration, intra-arterial; infusion technique, each additional hour (List separately in addition to code for primary procedure) [not covered for liver metastases from breast cancer]
96425	Chemotherapy administration, intra-arterial; infusion technique, initiation of prolonged infusion (more than 8 hours), requiring the use of a portable or implantable pump [not covered for liver metastases from breast cancer]
96522	Refilling and maintenance of implantable pump or reservoir for drug delivery, systemic (e.g., intravenous, intra-arterial)
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-10 codes covered if selection criteria are met:
C22.0	Liver cell carcinoma [hepatocellular cancers (HCC) without extrahepatic spread]
ICD-10 codes not covered for indications listed in the CPB:
C22.9	Malignant neoplasm of the liver, not specified as primary or secondary
C78.7	Secondary malignant neoplasm of liver and intrahepatic bile duct
Chemoembolization:
ICD-10 codes covered if selection criteria are met:
C22.0 - C22.9	Malignant neoplasm of the liver and intrahepatic bile ducts [unresectable]
C25.0 - C25.9	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)]
C69.40 - C69.42	Malignant neoplasm of ciliary body[with liver-only metastases]
C7A.0 - C7A.098	Malignant carcinoid tumors
C7B.02	Secondary carcinoid tumors of liver
Z76.82	Awaiting organ transplant status [Preoperative hepatic artery chemoembolization followed by orthotopic liver transplantation for HCC]
ICD-10 codes not covered for indications listed in the CPB:
C15.3 - C15.9	Malignant neoplasm of esophagus
C18.0 - C18.9	Malignant neoplasm of colon
C47.0 - C47.9, C49.0 - C49.9	Malignant neoplasm of connective tissue and other soft tissue [rhabdomyosarcoma]
C43.0 - C43.9, D03.0 - D03.9	Malignant melanoma and melanoma in situ of skin
C50.011 - C50.929	Malignant neoplasm of breast
C53.0 - C53.9	Malignant neoplasm of cervix uteri
C78.7	Secondary malignant neoplasm of liver and intrahepatic bile duct [palliative treatment of liver metastases from other non-neuroendocrine primaries (e.g., cervical cancer, colon cancer, melanoma, or unknown primaries)]
C80.1	Malignant (primary) neoplasm, unspecified
Z85.3	Personal history of malignant neoplasm of breast
Intra-hepatic chemotherapy:
ICD-10 codes covered if selection criteria are met:
C18.0 - C21.8	Malignant neoplasm of colon, rectum, rectosigmoid junction, and anus [not covered for "one-shot" arterial chemotherapy or transarterial gene therapy]
ICD-10 codes not covered for indications listed in the CPB:
C22.0 - C22.9	Malignant neoplasm of the liver and intrahepatic bile ducts [liver primary]
C50.011 - C50.929	Malignant neoplasm of breast
C78.7	Secondary malignant neoplasm of liver and intrahepatic bile duct [breast cancer]
Intra-hepatic microspheres:
ICD-10 codes covered if selection criteria are met:
C18.0 - C21.8	Malignant neoplasm of colon, rectum, rectosigmoid junction, and anus [unresectable liver tumors from primary colorectal cancer]
C22.0 - C22.9	Malignant neoplasm of the liver and intrahepatic bile ducts [unresectable primary HCC]
C23	Malignant neoplasm of gallbladder
C25.0 - C25.9	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)]
C7A.00 - C7A.098	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)]
C7B.02	Secondary carcinoid tumors of liver
C78.7	Secondary malignant neoplasm of liver and intrahepatic bile duct [not covered for liver metastases from uveal melanoma]
C78.80 - C78.89	Secondary malignant neoplasm of other and unspecified digestive organs
Drug-Eluting Beads Trans-Arterial Chemoembolization:
ICD-10 codes not covered for indications listed in the CPB:
C22.0 - C22.9	Malignant neoplasm of the liver and intrahepatic bile ducts
C47.0 - C47.9, C49.0 - C49.9	Malignant neoplasm of connective tissue and other soft tissue [leiomyosarcoma]
C78.7	Secondary malignant neoplasm of liver and intrahepatic bile duct [liver dominant]

The above policy is based on the following references: