Neuroendocrine Tumors

Transcatheter arterial chemoembolization (TACE) is considered medically necessary as palliative treatment for patients with:

• neuroendocrine tumors (e.g., carcinoid tumors, pancreatic islet cell tumors) with hepatic metastases when systemic therapy has failed to control symptoms such as carcinoid syndrome (e.g., debilitating flushing, wheezing, and diarrhea); or
• symptoms from non-carcinoid neuroendocrine tumors (e.g., hypoglycemia, severe diabetes, Zollinger-Ellison Syndrome); or
• symptoms due to hepatic tumor bulk (e.g., pain).

Hepatocellular Carcinoma

TACE is considered medically necessary as a primary treatment for surgically unresectable primary hepatocellular carcinoma (HCC), or , as a bridge to liver transplantation, when all of the following criteria are met:

• the patient has preserved liver function defined as Childs-Turcotte-Pugh Class A or B
• the patient has 3 or fewer encapsulated nodules that are less than 5 cm in diameter
• the patient has no evidence of extra-hepatic metastases
• the patient has no evidence of severe renal function impairment
• the patient has no evidence of portal hypertension.

TACE is considered medically necessary as a palliative treatment for hepatocellular carcinoma when there are significant symptoms related to tumor bulk (e.g., pain).

Metastatic Disease of the Liver

TACE is considered medically necessary as a palliative treatment for symptoms related to tumor bulk (e.g., pain).

Investigational/Not Medically Necessary:

TACE is considered investigational/not medically necessary , when the above criteria are not met; and for all other indications, including but not limited to, palliative treatment of either primary or secondary malignant disease of the liver that is not associated with a specific liver-related symptom.

TACE as Palliative Treatment for Neuroendocrine Tumors and Metastatic Liver Disease

For patients with hepatic metastasis from neuroendocrine tumors, the data confirms that chemoembolization has a role in the palliative care of patients with various neuroendocrine tumor symptoms such as carcinoid syndrome (e.g., severe flushing, wheezing, and diarrhea), Zollinger-Ellison Syndrome (multiple bleeding gastrointestinal ulcers), hypoglycemia, severe diabetes, and other neuroendocrine-related manifestations. The treatment has been shown to be useful in significantly diminishing the effect of these symptoms on the patient. Consequently, TACE can produce significant improvements in the quality of life for individuals with neuroendocrine tumors. TACE is also known to improve symptoms (e.g. pain) attributable to the effect of tumor bulk associated with either primary or metastatic liver disease through shrinkage of tumor size.

TACE as Treatment for Surgically Unresectable Primary Hepatocellular Carcinoma (HCC)

Several randomized controlled trials demonstrate a small but significant increase in survival in patients with unresectable hepatic tumors who meet specific selection criteria. Preserved liver function, 3 or fewer encapsulated nodules, which are less than 5 cm in diameter, absence of extra-hepatic metastases, no evidence of severe renal function impairment, and no evidence of portal hypertension are important factors in selecting the appropriate patients and are specifically identified in several studies as a key aspect of the success of TACE treatment.  The evidence indicates that those patients who do not meet these criteria do not respond adequately to TACE therapy and receive little or no benefit from the treatment.

TACE has also been studied for other indications including large HCC, preoperative shrinkage of resectable HCC, and for tumor types other than HCC and neuroendocrine tumors. Cheng and colleagues (2005) evaluated the value and limitation of postoperative TACE in preventing recurrence of HCC. In this retrospective study, the authors compared the recurrence rates for a group of 987 patients with HCC treated with TACE compared to a control group of 643 postoperative patients with HCC who did not receive TACE. The 6-, 12-, and 18-month recurrence rates for the TACE group compared to the non-TACE group were 22.2% vs 61.6%, 78.0% vs 74.7% and 88.6% vs 80.1%. There were also significant differences between the recurrence rates of the two groups at 6 months (P<0.0001). The authors concluded that TACE has a good effect of preventing recurrence of HCC at  6 months, but the rate of recurrence is less satisfactory in a longer period. The evidence does not demonstrate that TACE results in a significant advantage in quality of life or length of survival for these conditions.

TACE as a Bridge to Transplant

The role of TACE in the management of patients with HCC who are awaiting liver transplantation is an indication that has been explored in various settings; as a technique to prevent tumor progression while on the waiting list, to downstage tumors such that the patient is considered a better candidate for liver transplantation, and to decrease the incidence of post-transplant recurrence in patients with larger (T3) tumors. These indications are in part related to the current United Network for Organ Sharing (UNOS) liver allocation system referred to as MELD (model for end-stage liver disease) for adult patients awaiting liver transplantation. The MELD score is a continuous disease severity scale incorporating bilirubin, prothrombin time (i.e., international normalized ratio-INR), and creatinine into an equation, producing a number that ranges from 1 to 40. Aside from those in fulminant liver failure, donor livers are prioritized to those with the highest MELD number (UNOS, 2006). This scale predicts the risk of dying from liver disease except for those with HCC, who often have low MELD scores since bilirubin, INR, and creatinine levels are near normal. Therefore, patients with HCC are assigned additional allocation points according to the size and number (T stage) of tumor nodules as follows:

• T1: one nodule ≤ 1.9 cm
• T2: one nodule between 2.0 - 5.0 cm, or two or three nodules each < 3.0 cm 
• T3: one nodule > 5.0 cm, or two or three nodules with at least one > 3.0 cm

As specified in UNOS’s December 2006 revision, a candidate with Stage II HCC, in accordance with the American Liver Tumor Study Group Modified Tumor-Node-Metastasis (TNM) Staging Classification, that meets all of the medical criteria specified in Section 3.6.4.4 (i) and (ii) of the UNOS policy, may receive extra priority on the waiting list. A candidate with an HCC tumor that is greater than or equal to 2 cm and less than 5 cm, or, no more than 3 lesions, the largest being less 3 cm in size (Stage T2 tumors) may be registered as a MELD/PELD score equivalent to a 15% probability of candidate death within 3 months. 

UNOS sought to balance the risk of death on the waiting list against risk of recurrence after transplant. Patients with T1 lesions are considered at low risk of death on the waiting list, while those with T3 lesions are at high risk of post-transplant recurrence, and are generally not considered transplant candidates. Patients with T2 tumors have an increased risk of dying while on the waiting list compared with T1 lesions, and an acceptable risk of post-transplant tumor recurrence. Therefore, UNOS criteria prioritize T2 HCC by allocating additional points equivalent to a MELD score predicting a 15% probability of death within 3 months. This definition of T2 lesions is often referred to as the “Milan criteria,” in reference to a key 1996 study that examined the recurrence rate of HCC according to the size of the initial tumor (Mazzaferro, 1996). Liver transplantation for those with T3 HCC is not prohibited, but these patients do not receive any priority on the waiting list. All patients with HCC awaiting transplantation are reassessed at 3-month intervals. Those whose tumors have progressed and are no longer T2 tumors will lose the additional allocation points.

Therefore, the UNOS allocation system provides incentives to use loco-regional therapies to downsize tumors to T2 status and to prevent progression while on the waiting list. In addition, the UNOS policy appears to implicitly recognize the role of loco-regional therapy in the pretransplant setting. For example, section 3.6.4.4 (i) of the UNOS policy regarding the workup of patients with HCC states as follows, “In addition, the patient must have at least one of the following: vascular blush corresponding to the area of suspicion seen on the above imaging studies, an alpha-fetoprotein level of >200 ng/ml, an arteriogram confirming a tumor, a biopsy confirming HCC, chemoembolization of lesion, radiofrequency, cryo, or chemical ablation of lesion” (UNOS, 2006).

TACE as a Technique to Prevent Tumor Progression While on the Transplant Wait List

Several studies have reported dropout rates of wait-listed patients treated with loco-regional therapy. These studies lacked controlled data making it difficult to assess contributions of loco-therapy to time on the waiting list. In addition, after a 2002 revision in the UNOS liver allocation policy, wait times for patients with HCC meeting the “Milan criteria” have now declined.

Given these limitations the following case series have been reported. Graziadei and colleagues (2003) reported on 48 patients with HCC awaiting transplantation; all underwent TACE every 6 to 8 weeks until a complete response or a donor organ became available. No patients were removed from the list due to tumor progression, and the mean waiting time was 178 +/- 105 days. Maddala and colleagues (2004) studied the dropout rates of 54 patients receiving TACE while awaiting transplantation. During a median waiting time of 211 days (range 28–1,099 days), the dropout rate was 15%. More recently, Fisher and colleagues (2004) reported on 33 patients who received multimodality ablation therapy, consisting primarily of radiofrequency ablation or TACE. Five patients (12%) were removed from the waiting list after waits of 5 to 14 months. In this protocol, patients with tumors >5 cm were not considered transplant candidates until the tumor was completely ablated using TACE, radiofrequency ablation (RFA), or another technique. Yamashiki and colleagues (2005) reported on 288 patients given various ablative therapies; the dropout rate due to tumor progression at 1 and 3 years was 6.25 and 23%, respectively. Tumors greater than 3 cm affected the dropout rate due to tumor progression. 

A systematic review by Obed and colleagues (2007) assessed the outcome of patients who underwent TACE for HCC and subsequently liver transplantation (OLT), irrespective of tumor size when no tumor progression was observed. Records, imaging studies and pathology of 84 patients with HCC were reviewed. Ten patients were not treated at all, 67 patients had TACE and 35 were listed for OLT. Tumor progression was monitored by ultrasound and alpha-fetoprotein (AFP) level every 6 weeks. Fifteen patients showed signs of tumor progression without transplantation. The remaining 20 patients underwent OLT. Further records of 7 patients with HCC seen in histological examination after OLT were included. The authors reported that the patients after TACE without tumor progression underwent transplantation and had a median survival of 92.3 months. Patients who did not qualify for liver transplantation or had signs of tumor progression had a median survival of 8.4 months. The patients without treatment had a median survival of 3.8 months. Independent of International Union Against Cancer (UICC) stages, the patients without tumor progression and subsequent OLT had longer median survival. No significant difference was seen in the OLT treated patients if they did not fulfill the Milan criteria. The authors concluded that the selection of patients for OLT based on tumor progression results in good survival, citing the evaluation of patients with HCC should be based not only on tumor size and number of foci but also on tumor progression and growth behavior under therapy.

The Society of Interventional Radiology’s Position Statement on Chemoembolization of Hepatic Malignancies (Brown, 2006) cites the critical role chemoembolization plays in the prevention of progression of HCC until a donor liver becomes available. The position taken is that, based on the available literature (Fischer, 2004), chemoembolization as a bridge to transplantation is an option in permitting eventual cure by inhibiting tumor growth in this subset of patients so they can remain on the transplant wait list. 

TACE to Downgrade HCC Prior to Transplant

Yao and colleagues (2005) reported on a case series of 30 patients with HCC who underwent a variety of loco-regional therapies including TACE, specifically to downstage tumors to meet the University of California at San Francisco (UCSF) transplant criteria. Eligibility for loco-regional therapy seeking to downstage patients included either 1 nodule between 5 and 8 cm in diameter; 2 or 3 nodules with at least 1 between 3 and 5 cm in diameter, with sum of diameters no greater than 8 cm; or 4 or 5 nodules all less than or equal to 3 cm, with sum of diameters less than 8 cm. Among the 30 patients, 21 (70%) met the criteria for loco-regional therapy and 16 of these were successfully downstaged and underwent transplantation. No tumors recurred at a median follow-up of 16 months. The authors concluded that downstaging can be successfully achieved in most patients, but that data regarding tumor recurrence requires longer follow-up.

TACE as an Ablative Technique to Reduce Recurrence Rates in Those with T3 Lesions

Published literature reflects an ongoing discussion as to whether the UNOS allocation criteria should expand to include patients with larger tumors (Fernandez, 2003; Sauer, 2005; Yao, 2001; Yao, 2002). Certainly some patients with T3 lesions apparently are cured with liver transplant, although most experience recurrent tumor. For example, in a decisive 1996 study, the 4-year recurrence-free survival was 92% in those who met the “Milan criteria” compared to 59% in those who did not; additional studies confirm this difference in recurrence-free survival rate (Sauer, 2005). However, other institutions have reported similar outcomes with expanded criteria. For example, Yao and colleagues (2002) at UCSF reported similar recurrence-free survival after transplant in patients with T2 and a subset of those with T3 tumors. This T3 subset was defined as a single lesion ≤ 6.5 cm or ≤ 3 lesions with none < 3 cm and with a sum of tumor diameters ≤ 8 cm. These expanded criteria are known as the UCSF criteria (Merli, 2005).

The question is whether TACE may decrease recurrence rate in patients meeting these UCSF criteria. Yao and colleagues published a detailed analysis of 121 patients with HCC who underwent transplantation (Yao, 2005). Seventy-eight patients (64%) had T2 lesions, while an additional 27 patients (22.3%) met the expanded UCSF criteria, termed T3A lesions. The remaining patients had T1, T3B, or T4 lesions. Individual patients received a variety of pre-operative loco-regional therapies, including TACE or ablative therapies, such as percutaneous ethanol injection (PEI), RFA, or combined therapies. TACE was used most commonly in 43.5% of patients. However, more than half these patients received TACE within 24 hours of transplant to decrease the risk of tumor dissemination at the time of hepatectomy. A total of 38.7% of patients did not receive preoperative loco-regional therapy. The 1- and 5-year recurrence-free survival was similar in those with T2 and T3A lesions, while the corresponding recurrence rates were significantly lower for those with T3B and T4 lesions.

The authors also compared recurrence-free survival of those who did and did not receive loco-regional therapy. For those with T2 lesions, the recurrence rates were similar whether or not the patient received loco-regional therapy. However, for T3 lesions (including both T3A and T3B), the 5-year recurrence-free survival was 85.9% for those who received loco-regional therapy compared to 51.4% in those who did not. When the data for T2 and T3 lesions were grouped together, the 5-year recurrence-free survival was 93.8% for those who received loco-regional therapy compared to 80.6% in those who did not. The authors concluded that preoperative loco-regional therapy may confer a survival benefit in those with T2 or T3 lesions.

The authors note several limitations to the study, including the retrospective nature of the data, and the marginal statistical significance of the improved survival given the small numbers of patients in each subgroup. For example, only 19 patients were in the T3A (i.e., UCSF expanded criteria) subgroup. In addition, no protocol specified which type of loco-regional therapy to offer different patients. These therapies are only offered to those patients with adequate liver reserve; such patients may have an improved outcome regardless of the preoperative management. An editorial accompanying the article further underscores the limitations in interpreting these data, and suggests that TACE given immediately prior to surgery may not be as effective as TACE given multiple times in the pretransplant period (Palmer, 2005).

Summary

Transcatheter arterial chemoembolization (TACE) is an interventional treatment option as palliative therapy for patients with neuroendocrine or symptomatic HCC tumors, for selected patients with primary, surgically unresectable HCC, or as a bridge for those patients awaiting liver transplantation. TACE may improve the health outcomes for these patients as measured by quality of life parameters (symptom control) or improved survival rates.

Description of Major Disease

Hepatocellular carcinoma (HCC) is one of the most common fatal malignancies worldwide, with more than 530,000 new cases diagnosed annually (El-Serag, 2002). Malignant hepatic tumors may be primary, such as hepatocellular carcinoma or arise from metastases from other cancers such as colorectal carcinoma. Surgical excision is the optimal treatment for hepatocellular primaries, but many tumors are unresectable due to size, location or inadequate liver reserve secondary to a cirrhotic liver. In patients with unresectable disease, liver transplantation is considered the other curative option. Surgical excision of metastatic liver disease is generally not considered curative, with the exception of patients with isolated liver metastases without any other evidence of disease. 

Neuroendocrine tumors may also involve the liver, where hormone production can cause systemic symptoms. The most common neuroendocrine tumor is the carcinoid tumor where excessive hormone production is associated with the carcinoid syndrome, characterized by debilitating flushing, wheezing and diarrhea. Pancreatic endocrine (i.e., islet cell) tumors that produce gastrin, insulin or other pancreatic hormones are unusual types of neuroendocrine tumors. Pancreatic endocrine tumors must be distinguished from the more common pancreatic epithelial tumors that arise from the exocrine portion of the pancreas. Surgical resection is typically not possible for neuroendocrine tumors, and treatment may be focused on palliation of specific systemic symptoms. 

Description of Technologies

Transarterial chemoembolization (TACE) involves the injection of chemotherapeutic drugs and embolizing agents into the branch of the hepatic artery supplying a tumor. The goal of this procedure is to deliver the chemotherapeutic agents directly to the tumor and to block blood flow to the tumor.

Prior to beginning the procedure, angiography is performed to visualize the blood vessels of the liver. Subsequently a local anesthetic is applied and a thin catheter is introduced through a small incision into the femoral artery in the groin. Through television monitoring, the proceduralist guides the catheter into the main artery feeding the liver. The catheter is then guided into the branches feeding the tumor and the chemoembolic material is injected. Repeated x-ray pictures will be taken to confirm that the tumor has been optimally treated. This procedure is usually performed by an interventional radiologist.

Proposed Benefits

TACE is performed with the intention of reducing the size and/or growth rate of hepatocellular carcinoma. TACE is purported to increase survival length and quality of life due to the resulting decreased tumor burden. In addition, TACE has been proposed for use as a palliative treatment of symptoms associated with functioning neuroendocrine tumors involving the liver. In a small subset of patients with metastatic disease, TACE may be used to treat specific symptoms related to tumor bulk (e.g. pain). Chemoembolization also plays a role in a select group of patients by inhibiting tumor growth in HCC so they can remain on the transplant wait list.

Possible Risks

Such risks may include an allergic or other reaction to the contrast dye used to visualize the arteries. In addition, fevers, fatigue, and nausea may result from the chemotherapy. In about one in 20 procedures, significant complications may occur that usually consist of infection or damage to the liver. The risk of death from the procedure is about 1%, usually from liver failure.

Childs-Turcotte-Pugh (CTP): a scoring system for severity of liver disease and likelihood of survival based on the presence of: degenerative disease of the brain (encephalopathy), the escape or accumulation of fluid in the abdominal cavity (ascites), laboratory measures of various substances in the blood (see table below), and the presence of other co-existing diseases; after calculating the CTP score using a table similar to the one below, patients can be classified into one of three categories:

• Childs A (5-6 points): 10 year survival 80-90%;
• Childs B (7-9 points): 5 year survival 60-80% and
• Childs C (10-15 points): 2 year survival < 50%.

Encapsulated nodules: any group of abnormal cells confined to a specific area, surrounded by a covering of specialized cells called a capsule

Extra-hepatic metastases: tumors that have spread outside the liver that originate from HCC or other primary liver tumors

Hepatic metastases: cancer that has spread from its original location in the body to the liver

Palliative treatment: treatment given for relief of symptoms and pain rather than effecting a cure

Primary hepatocellular cancer: a cancer that originates within liver cells, as opposed to having spread to the liver from other organs

Transcatheter arterial chemoembolization (TACE): a surgical procedure where a thin tube is inserted into an artery that leads to an organ that has a tumor; the tube is then used to inject drugs into the organ near the tumor in an attempt to shrink or kill the tumor

The following codes for treatments and procedures applicable to this policy are included below for informational purposes.  Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member’s contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:

CPT

ICD-9 Diagnosis

When services are Investigational/Not Medically Necessary:

For the procedure codes listed above, when criteria are not met, for all other tumor diagnoses not listed; or when the code describes a procedure indicated in the Policy section as investigational/not medically necessary.

Peer Reviewed Publications:

1. Bronowichi J, Boudjema K, Chone L, et al. Comparison of resection, liver transplantation and transcatheter oily chemoembolization in the treatment of hepatocellular carcinoma. J Hepatol. 1996; 24:293-300.
2. Brown DB, Geschwind JF, Soulen M, et al. Society of Interventional Radiology (SIR) position statement on chemoembolization of hepatic malignancies. Society of Interventional Radiology. J Vasc Interv Radiol. 2006; 17(2):217-223. Available at:  http://www.sirweb.org/clinical/cpg/217.pdf. Accessed on January 9, 2007.
3. Bruix J, Llovet JM, Castells A, et al. Transarterial embolization vs symptomatic treatment in patients with advanced HCC: results of a randomized, control trial in a single institution. Hepatology. 1998; 27:1578-1583.
4. Camma C, Schepis F, Orlando A, et al. Transarterial chemoembolization for unresectable hepatocellular carcinoma: Meta-analysis of randomized controlled trials. Radiology. 2002; 224(1):47-54.
5. Cheng HY, Wang X, Chen D, et al. The value and limitation of transcatheter arterial chemoembolization in preventing recurrence of resected hepatocellular carcinoma. World J Gastroenterol. 2005 Jun 21; 11(23):3644-3646.
6. Di Carlo V, Ferrari G, et al.  Pre-operative chemoembolization of hepatocellular carcinoma in cirrhotic patients. Hepato-Gastroenterology. 1998; 45:1950-1954. 
7. Drouglas JG, Lowell B, Taylor K.  Hepatic artery chemoembolization for management of patients with advanced carcinoid tumors. Am J Surg. 1998; 175:408-412.
8. El-Serag HB. Hepatocellular carcinoma: an epidemiologic view. J Clin Gastroenterol. 2002; 35S:72-78.
9. Fernandez GA, Robles R, Marin C, et al. Can we expand the indications for liver transplantation among hepatocellular carcinoma patients with increased tumor size? Transplant Proc. 2003; 35(5):1818-1829.
10. Fisher RA, Maluf D, Cotterell AH, et al. Non-resective ablative therapy for hepatocellular carcinoma: effectiveness measured by intention-to-treat and dropout from liver transplant waiting list. Clin Transplant. 2004; 18(5):502-512. 
11. Georgiades C, Liapi E, Frangakis C, et al. Prognostic accuracy of 12 liver staging systems in patients with unresectable hepatocellular carcinoma treated with transarterial chemoembolization. J Vasc Interv Radiol. 2006; 17:1619-1624.
12. Gerunda GE, Neri D, Merenda R, et al.  Role of transarterial chemoembolization before liver resection for hepatocarcinoma. Liver Transplant. 2000; 6(5):619-626.
13. Graziadei IW, Sandmueller H, Waldenberger P, et al. Chemoembolization followed by liver transplantation for hepatocellular carcinoma impedes tumor progression while on the waiting list and leads to excellent outcome. Liver Transpl. 2003; 9(6):557-563.
14. Koda M, Murawaki Y, Mitsuda A, et al.  Combination therapy with transcatheter arterial chemoembolization and percutaneous ethanol injection compared with percutaneous ethanol injection alone for patients with small hepatocellular carcinoma.  Cancer. 2001; 92(6):1516-1524.
15. Little SA, Fong Y.  Hepatocellular carcinoma: current surgical management.  Seminars in Oncology. 2001; 28 (5):474-486.
16. Llovet JM, Real ML, Montaña X, et al.  Arterial embolization or chemoembolization versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomized controlled trial.  Lancet. 2002; 359:1734-1739.
17. Lo C, Ngan H, Tso W, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma.  Hepatology.  2002; 35:1164-1171.
18. Lopez RR, Pan S, Hoffman AL, et al.  Comparison of transarterial chemoembolization in patients with unresectable, diffuse vs. focal hepatocellular carcinoma.  Arch Surg.  2002; 137:653-658.
19. Maddala YK, Stadheim L, Andrews JC, et al. Drop-out rates of patients with hepatocellular cancer listed for liver transplantation: outcome with chemoembolization. Liver Transpl. 2004; 10(3):449-455.
20. Malogolowkin MH, Stanley P, Steele D, et al.  Feasibility and toxicity of chemoembolization for children with liver tumors.  J Clin Oncol. 2000; 18(6):1279-1284.
21. Manjo PE, Adam R, Bsimuth H, et al.  Influence of preoperative transarterial lipiodol chemoembolization on resection and transplantation for hepatocellular carcinoma in patients with cirrhosis. Ann Surg. 1997; 226(6): 688-703.
22. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996; 334(11):693-699.
23. Merli M, Nicolini G, Gentilli F, et al. Predictive factors of outcome after liver transplantation in patients with cirrhosis and hepatocellular carcinoma. Transplant Proc. 2005; 37(6);2535-2540.
24. Obed A, Behan A, Pullmann K, et al. Patients without hepatocellular carcinoma progression after transarterial chemoembolization benefit from liver transplantation. World J Gastroenterol. 2007 Feb 7; 13(5):761-767.
25. Oldhafer KJ, Chavan A, Fruhauf NR, et al.  Arterial chemoembolization before liver transplantation in patients with HCC: marked tumor necrosis, but no survival benefit?  J Hepatology. 1998; 29:953-959.
26. O’Suilleabhain CB, Poon RTB, Yong JL, et al.  Factors predictive of 5-year survival after transarterial chemoembolization for inoperable hepatocellular carcinoma.  British Journal of Surgery. 2003; 90:325-331.
27. Paye F, Jagot P, Vilgrain V, et al.  Preoperative chemoembolization of hepatocellular carcinoma.  Arch Surg. 1998; 133:767-772.
28. Pelletier G, Ducreux M, Gay F,  et al.  Treatment of unresectable hepatocellular carcinoma with lipiodol chemoembolization: a multicenter randomized trial. J Hepatology. 1998; 29:129-134.
29. Palmer DH, Johnson PJ. Pre-operative loco-regional therapy and liver transplantation for hepatocellular carcinoma: time for a randomized controlled trial. Am J Transplant. 2005; 5(4 pt 1):641-642.
30. Poyanli A, Rozanes B, Acuna S, et al. Palliative treatment of hepatocellular carcinoma by chemoembolization.   Acta Radiologica. 2001; 42:602-607.
31. Roche A, Girish BV, de Baere T, et al.  Trans-catheter arterial chemoembolization as first-line treatment for hepatic metastases from endocrine tumors.  Eur Radiol. 2003; 13:136-140.
32. Rose DM, Chapman WC, et al. Transcatheter arterial chemoembolization as primary treatment for hepatocellular carcinoma. Am J Surg. 1999; 177(5):405-410.
33. Roayaie S, Frischer J, Emre SH, et al.  Long-term results with multimodal adjuvant therapy and liver transplantation for the treatment of hepatocellular carcinomas larger than 5 centimeters. Ann Surg. 2002; 235(4):533-539.
34. Sauer P, Kraus TW, Schemmer P, et al. Lover transplantation fro hepatocellular carcinoma: Is there evidence for expanding the selection criteria? Transplantation. 2005.; 80(1 suppl):S105-108.
35. Seiki T, Tamai T, Nakagawa T, et al.  Combination therapy with transcatheter arterial chemoembolization and percutaneous microwave coagulation therapy for hepatocellular carcinoma. Cancer. 2000; 89(6):1245-1251.
36. Sugo H, Futagawa S, Beppu T, et al.  Role of preoperative transcatheter arterial chemoembolization for resectable hepatocellular carcinoma:  relation between postoperative course and the pattern of tumor recurrence.  World J Surg. 2003; 27:1295-1299.
37. Sun H-C, Tang Z-Y.  Preventive treatments for recurrence after curative resection of hepatocellular carcinoma: a literature review of randomized controlled trials.  World J Gastroenterol. 2003; 9:635-640.
38. Sullivan K. Hepatic artery chemoembolization.  Sem Oncol. 2002; 29(2):145-151.
39. Treviasani F, De Notariis S, Rossi C.  Randomized control trials on chemoembolization for hepatocellular carcinoma.  J Clin Gastroenterol. 2001; 32(5):383-389.
40. Venook AP. Embolization and chemoembolization therapy for neuroendocrine tumors. Cur Opin Oncol. 1999; 11(1):38-41.
41. Yamakado K, Nakatsuka A, Tanaka N, et al.  Long-term follow-up arterial chemoembolization combined with transportal ethanol injection used to treat hepatocellular carcinoma.  JVIR. 1999; 10(5):641-647.
42. Yamashiki N, Tateishi R, Yoshida H, et al. Ablation therapy in containing extension of hepatocellular carcinoma: a simulative analysis of dropout from the waiting list for liver transplantation. Liver Transpl. 2005; 11(5):508-514.
43. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: comparison of the proposed USCF criteria with the Milan criteria and the Pittsburgh modified TNM criteria. Liver Transpl. 2002; 8(9):765-774.
44. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology. 2001; 33(6):1394-1403.
45. Yao FY, Hirose R, LaBerge JM, et al. A prospective study on downstaging of hepatocellular carcinoma prior to liver transplantation. Liver Transpl. 2005; 11(12):1505-1514.
46. Yao FY, Kinkhabwala M, LaBerge JM, et al. The impact of pre-operative loco-regional therapy on outcome after liver transplantation for hepatocellular carcinoma. Am J Transplant. 2005; 5(4 pt 1):795-804.

1. American Cancer Society. Cancer facts and figures 2006. Available at:  http://www.cancer.org/downloads/STT/CAFF2006PWSecured.pdf. Accessed on January 9, 2007. 
2. Hayes Inc. Hayes Medical Technology Directory. Chemoembolization for Primary Liver Cancer. Lansdale, PA: Hayes, Inc.; July 2002. Search updated March 18, 2006.
3. National Cancer Institute. Adult primary liver cancer (PDQâ): treatment. Available at:  http://www.cancer.gov/cancertopics/pdq/treatment/adult-primary-liver/ healthprofessional . Accessed on January 9, 2007.
4. United Network for Organ Sharing (UNOS). Policies: 3.6 Organ Distribution: Allocation of Livers. Revised December 14, 2006. Available at:  http://www.unos.org/policiesandbylaws/policies.asp?resources=true. Accessed on March 22, 2007.

Federal and State law, as well as contract language, including definitions and specific contract provisions/exclusions, take precedence over Medical Policy and must be considered first in determining eligibility for coverage. The member's contract benefits in effect on the date that services are rendered must be used. Medical Policy, which addresses medical efficacy, should be considered before utilizing medical opinion in adjudication. Medical technology is constantly evolving, and we reserve the right to review and update Medical Policy periodically.

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