1. Percutaneous Ethanol Injection

   Aetna considers percutaneous ethanol injection (PEI) medically necessary for the treatment of hepatocellular cancers (HCC) without extrahepatic 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.

2. Chemoembolization

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

   1. For symptomatic treatment of functional 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. Preoperative 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., colon cancer, melanoma, or unknown primaries) because there is inadequate evidence in the medical literature of the effectiveness of CE for these indications.

3. Intra-hepatic Chemotherapy

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

   Aetna considers intra-hepatic chemotherapy experimental and investigational for other indications, including treatment of liver primaries or metastases from other primaries besides colorectal cancer.

   Aetna considers “one-shot” arterial chemotherapy for members with liver metastases from colorectal cancer experimental and investigational.

   Aetna considers transarterially administered gene therapy experimental and investigational for primary and secondary liver malignancies.

4. Intra-hepatic Microspheres

   Aetna considers intra-hepatic microspheres (e.g., TheraSphere, MDS Nordion Inc., SIR-Spheres, Sirtex Medical Inc., San Diego, CA) medically necessary for members with unresectable HCC or unresectable liver tumors from primary colorectal cancer. 

   Aetna considers intra-hepatic microspheres experimental and investigational for other indications.

See also  CPB 274 - Ablation of Hepatic Lesions.

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

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

TACE 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 intranodular 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, chemoembolization (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 extrahepatic 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). 

Percutaneous ethanol injection (PEI) has been shown to be effective only in primary hepatocellular carcinoma with a limited number (fewer than 4) of small foci (less than 5 cm in diameter) and with no evidence of extrahepatic metastasis.  According to the medical literature, PEI is not suitable for persons with coagulopathy or ascites.

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 overall survival (OS) is unclear.  These investigators quantitatively summarized the results of randomized controlled trials (RCT) 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, hazard ratios (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 two 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 overall survival.  A new approach in treating these patients is administration of microspheres via hepatic artery branches with subsequent deposition in the tumor terminal vasculature.  This method could provide an approximately 3-fold or greater radiation dose in tumor nodules relative to normal liver.  Previous studies have demonstrated that yttrium-90 embedded into non-biodegradable glass microspheres (TheraSphere, MDS Nordion Inc., Kanata, Ontario, Canada) can be administered safely by intra-hepatic arterial injection to patients with HCC and underlying cirrhosis at a dose of 100 Gy.  A recent study (Dancey et al, 2000) reported that intra-hepatic yttrium-90 microspheres appears to be beneficial for patients with non-resectable HCC with less toxicity than systemic or hepatic arterial chemotherapy or hepatic arterial chemoembolization.

Dancey, et al. (2000) indicated that the following criteria be used to select appropriate patients for administration of intrahepatic 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 colorectal cancer (see discussion of Sir-Spheres below): 

1. Histologically confirmed non-resectable lesion confined to the liver and at least 1 measurable lesion; and 

2. Eastern Cooperative Oncology Group performance status score less than or equal to 3

   1. Estimated life expectancy greater than or equal to 12 weeks 
   2. Absolute granulocyte count greater than or equal to 2.0 x 10 9/L 
   3. Platelet count greater than or equal to 100 x 10⁹/L 
   4. Prothrombin time (PT) and activated partial prothrombin time (APTT) within normal limits [PT = 11.0 to 12.5 seconds; APTT = 30 to 40 seconds] 
   5. 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] 
   6. 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] 

   7. 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); and 

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

6. At least 1 month post other chemotherapy or surgery.

The following exclusion criteria apply:  

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

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

In the United States, Sir-Spheres are indicated for the treatment of unresectable metastatic liver tumors from primary colorectal cancer with adjuvant intra-hepatic artery chemotherapy (IHAC) of FUDR (floxuridine).  FDA approval of Sir-Spheres was based on the results of a randomized, controlled clinical trial involving 70 persons with colorectal cancer 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 complete response, and 16 had a partial response.  By comparison, one patient receiving FUDR alone achieved a complete response and seven had a partial response.  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 colorectal cancer in the liver is considered unresectable. According to the FDA-approved labeling, metastatic colorectal cancer may be considered nonresectable in any of the following circumstances:

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

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

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

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

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

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

• Had previous external beam radiation therapy to the liver, or
• Ascites or are in clinical liver failure, or
• Markedly abnormal synthetic and excretory liver function tests (LTFs), or
• Greater than 20% lung shunting of the hepatic artery blood flow determined by technetium MAA scan, 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, or
• Disseminated extra-hepatic malignant disease, or
• Been treated with capecitabine within the two previous months, or who will be treated with capecitabine at any time following treatment with Sir-Spheres, or
• Portal vein thrombosis.

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.