Coverage Policy Manual
Policy #: 2008006
Category: Medicine
Initiated: January 2008
Last Review: October 2018
  Transcatheter Arterial Chemoembolization (TACE) to Treat Primary or Metastatic Liver Malignancies

Description:
Transcatheter arterial chemoembolization (TACE) of the liver is a proposed alternative to conventional systemic or intra-arterial chemotherapy, and to various nonsurgical ablative techniques, to treat resectable and nonresectable tumors. The rationale for TACE is that infusions of viscous material containing one or more antineoplastic agents may exert synergistic effects: cytotoxicity from the chemotherapy, potentiated by anoxia in the infarcted region. The beneficial effect of chemoembolization may be further potentiated by labeling the infusate with radioactive isotopes for localized radiotherapy. The liver is especially amenable to such an approach, given its distinct lobular anatomy, the existence of 2 independent blood supplies, and the ability of healthy hepatic tissue to grow and thus compensate for tissue mass lost during chemoembolization. Another rationale is that TACE delivers effective local doses, while possibly minimizing systemic toxicities associated with oral or intravenous chemotherapy.
 
TACE of the liver is associated with its own constellation of potentially life-threatening toxicities and complications, including severe postembolization syndrome, hepatic insufficiency, abscess, or infarction. TACE has been investigated to treat resectable, unresectable, and recurrent hepatocellular carcinoma, to treat liver metastases, and in the liver transplant setting. Treatment alternatives include resection when possible, chemotherapy administered systemically or by hepatic artery infusion (HAI). HAI involves continuous infusion of chemotherapy with an implanted pump, while TACE is administered episodically. Also, HAI does not involve the use of embolic material.
 
The TACE procedure requires hospitalization for placement of the hepatic artery catheter and workup to establish eligibility for chemoembolization. Prior to the procedure, the patency of the portal vein must be demonstrated to ensure an adequate post-treatment hepatic blood supply. With the patient under local anesthesia and mild sedation, a superselective catheter is inserted via the femoral artery and threaded into the hepatic artery. Angiography is then performed to delineate the hepatic vasculature, followed by injection of the embolic chemotherapy mixture. Embolic material varies, but may include a viscous collagen agent, polyvinyl alcohol particles, or ethiodized oil. Typically, only 1 lobe of the liver is treated during a single session, with subsequent embolization procedures scheduled from 5 days to 6 weeks later. In addition, since the embolized vessel recanalizes, chemoembolization can be repeated as many times as necessary.
 
RELATED POLICIES:
  • 1997255 – Hepatic Tumors, Ablative Procedures (Percutaneous Ethanol Injections, Acetic Acid Injections,  and Interstitial Laser Photocoagulation)
  • 2003061 - Brachytherapy, Radioembolization of Primary & Metastatic Tumors of the Liver with Therapeutic Microspheres
  • 2011078 - Microwave Ablation of Tumors
  • 2012062 - Radiofrequency Ablation of Primary or Metastic Liver Tumors
 

Policy/
Coverage:
Effective December 2010
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Transcatheter hepatic arterial chemoembolization meets member certificate of benefit primary coverage criteria for effectiveness for treatment of:
 
    • hepatocellular cancer that is unresectable but confined to the liver and not associated with portal vein thrombosis;
    •  liver metastasis in symptomatic patients with metastatic neuroendocrine tumors whose symptoms persist despite systemic therapy and who are not candidates for surgical resection;
    •  liver metastasis in patients with liver-dominant metastatic uveal melanoma:
    •  as a bridge to transplant in patients with hepatocellular cancer where the intent is to prevent further tumor growth and to maintain a patient’s candidacy for liver transplant when  all of the following patient characteristics apply:
        • a single tumor less than 5cm or no more than 3 tumors each less than 3 cm in size, AND
        • Absence of extrahepatic disease or vascular invasion, AND
        • Child-Pugh score of either A or B.  
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Transcatheter hepatic arterial chemoembolization  to treat liver metastases from any other tumors or for any indication not specifically listed as covered does not meet Primary Coverage Criteria and is not covered.  
 
For contracts that do not have Primary Coverage Criteria, transcatheter hepatic arterial chemoembolization  to treat liver metastases from any other tumors or for any indication not specifically listed as covered is considered investigational.  Investigational services are an exclusion in the member benefit certificate of coverage.
 
Transcatheter hepatic arterial chemoembolization as neoadjuvant or adjuvant therapy in hepatocellular cancer that is considered resectable does not meet Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For contracts that do not have Primary Coverage Criteria, transcatheter hepatic arterial chemoembolization as neoadjuvant or adjuvant therapy in hepatocellular cancer that is considered resectable is considered investigational.  Investigational services are an exclusion in the member benefit certificate of coverage.
 
Effective January 2008 through November 2010
 
Transcatheter hepatic arterial chemoembolization meets member certificate of benefit primary coverage criteria for effectiveness for treatment of:
 
    • hepatocellular cancer that is unresectable but confined to the liver and not associated with portal vein thrombosis;
    •  liver metastasis in symptomatic patients with metastatic neuroendocrine tumors whose symptoms persist despite systemic therapy and who are not candidates for surgical resection;
    •  liver metastasis in patients with liver-dominant metastatic uveal melanoma:
    •  as a bridge to transplant in patients with hepatocellular cancer where the intent is to prevent further tumor growth and to maintain a patient’s candidacy for liver transplant when  the following patient characteristics apply:  
        • a single tumor less than 5cm; or no more than 3 tumors each less than 3 cm in size, AND
        • absence of extrahepatic disease or vascular invasion,  AND
        • Child-Pugh score of either A or B.  
 
Transcatheter hepatic arterial chemoembolization  to treat liver metastases from any other tumors or for any indication not specifically listed as covered does not meet Primary Coverage Criteria and is not covered.  
 
For contracts that do not have Primary Coverage Criteria, transcatheter hepatic arterial chemoembolization  to treat liver metastases from any other tumors or for any indication not specifically listed as covered is considered investigational.  Investigational services are an exclusion in the member benefit certificate.
 

Rationale:
Due to the detail of the rationale, the complete document is not online. If you would like a hardcopy print, please email: codespecificinquiry@arkbluecross.com
 
A 2000 Technology Evaluation Center (TEC) Assessment evaluated TACE for the following indications:
    • patients with resectable primary hepatocellular carcinoma (HCC), in which outcomes were compared to those with surgery alone;
    • patients with HCC that has recurred after resection, in which outcomes were compared with systemic chemotherapy, hepatic artery infusion, and cytoreductive surgery;
    • patients with unresectable HCC, in which outcomes were compared with systemic chemotherapy, hepatic artery infusion, cytoreductive surgery, percutaneous ethanol injection, transcatheter embolization without drugs, or supportive care only;
    • patients with unresectable hepatic metastases from resected colorectal cancer, in which outcomes were compared with systemic chemotherapy and hepatic artery infusion; and
    • patients with hepatic metastases from neuroendocrine tumors (i.e., carcinoid or islet cell malignancies), in which outcomes were compared with cytoreductive surgery, medical management, and chemotherapy.
 
The  Assessment offered the following observations and conclusions:
    • Five randomized trials focused on the use of TACE to treat resectable hepatocellular carcinoma, either in the adjuvant or neoadjuvant setting. These trials reported inconsistent results in terms of survival rates. Treatment-related morbidity and mortality were not reported consistently across studies.
    • No randomized study focused on TACE to treat postoperative recurrent hepatocellular carcinoma, and data were insufficient to permit scientific conclusions on its effectiveness in this setting.
    • Three randomized trials focused on the use of TACE to treat unresectable hepatocellular carcinoma compared to supportive care. Survival did not differ significantly among groups in any of the trials.
    • There were no controlled trials focusing on patients with unresectable hepatic metastases from colon cancer. The outcomes of TACE in the available uncontrolled series appeared similar to outcomes reported of hepatic artery infusion and systemic chemotherapy. The available data also did not show superiority for either TACE or alternatives with respect to complication rates or treatment-related mortality.
    • There were no controlled trials comparing TACE to alternatives in the treatment of hepatic metastases from carcinoid or islet cell tumors. While 3 case series reported that TACE reduced symptoms due to excess hormone production, there was no information regarding the efficacy of medical management to control symptoms. Data were also inadequate to permit conclusions regarding tumor response rates and survival.
 
2006 Update
A MEDLINE (via PubMed) search was performed in January 2006 to identify relevant literature published since the 2000 TEC Assessment. The search identified over 500 citations on chemoembolization. Most were uncontrolled clinical series, case studies, or laboratory studies. Response to treatment and other outcomes are strongly influenced by the number and size of the tumor(s), location relative to major vessels, and presence of concurrent liver disease (e.g., cirrhosis, hepatitis).  The influence of these and other clinical characteristics on prognosis have given rise to at least 4 staging systems.  Outcome within any prognostic category, however, can still be highly variable, which raises questions regarding the validity of results in uncontrolled study cohorts, especially those that include patients with mixed prognostic characteristics as is common in the literature. (Multiple critical reviews recently have discussed the published data highlighting these concerns and the inconclusive or contradictory nature of the data.)  For these reasons, the discussion of recent literature is limited to reports from randomized, controlled trials.
 
Four randomized, controlled trials comparing TACE to alternative treatments have been published since the 2000 TEC Assessment.  Survival was the primary endpoint in 3 of 4 studies; the primary endpoint in the fourth, a randomized phase II trial, was overall response rate. None of these studies reported quality of life data or effects of TACE on palliation of symptoms.
 
Salman et al  randomized 50 patients with hepatic metastases from colorectal cancer to treatment with polyvinyl alcohol foam transarterial embolization (TAE) to TAE plus 5-fluorouracil and interferon (TACE). The study did not observe a difference in response rate, response duration, or survival for patients treated with TACE compared to those treated with TAE.
 
Koda et al reported a randomized comparison of TACE plus percutaneous ethanol injection (PEI) to PEI alone in 52 patients with “one to three HCC tumors measuring <3 cm in greatest dimension.” Post hoc subset analysis identified a significant survival benefit for TACE+PEI treatment among patients with smaller (i.e., less than 2 cm) tumors. Given that the clinical characteristics of patients in each arm bridged at least 2 prognostic categories for each major clinical characteristic (e.g., presence and etiology of concurrent liver disease, number of liver lesions, greatest tumor dimension) these subset analyses are, at best, hypothesis generating and require confirmation in separate trials.
 
The last 2 randomized, controlled trials compared TACE to conservative (i.e., symptomatic) treatment in patients with unresectable HCC. Both studies enrolled consecutive patients who met study criteria for unresectable HCC from among larger series of patents seeking treatment at the respective institutions. Patients in the Hong Kong study  tended to have more advanced disease based on Okuda stage, ECOG performance status, and presence of tumor-related symptoms. The studies used a similar embolization regimen (lipiodol and gelatin sponge) but different cytotoxic agents (doxorubicin or cisplatin). Both studies reported significantly increased response and overall survival rates following treatment with TACE; neither study reported an increase in serious or life-threatening treatment-related adverse events after TACE.
 
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 was not addressed in the 2000 TEC Assessment. TACE 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. All of these indications are in part related to the current UNOS liver allocation policy, which prioritizes patients for receiving donor livers.
 
UNOS Liver Allocation Policy
In 2002, UNOS introduced a new liver allocation system, model for end-stage liver disease (referred to as MELD) for adult patients awaiting liver transplant. 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. This scale accurately predicts the risk of dying from liver disease except for those with hepatocellular cancer (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
 
In considering how to allocate the scarce donor organs, UNOS sought to balance risk of death on the waiting list against risk of recurrence after transplant. Patients with T1 lesions were 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.  Note that 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 strong 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.”
 
TACE as a Technique to Prevent Tumor Progression While on the Waiting List
Several studies have reported dropout rates of wait-listed patients treated with loco-regional therapy. However, lacking controlled data, it is difficult to assess contributions of loco-regional therapy to time on the waiting list. In addition, in 2002, as discussed here, UNOS revised its liver allocation policy, such that 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 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.  None were removed from the list due to tumor progression, and mean waiting time was 178 +/- 105 days. Maddala and colleagues 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 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 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.
 
TACE to Downgrade HCC Prior to Transplant
Yao and colleagues 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) 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.
 
Ablative Techniques 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.  Certainly some patients with T3 lesions apparently are cured with liver transplant, although most experience recurrent tumor. For example, in the seminal 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.  However, other institutions have reported similar outcomes with expanded criteria. For example, Yao and colleagues 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 greater than 3 cm and with a sum of tumor diameters </= 8 cm. These expanded criteria are known as the UCSF criteria.
 
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.  Seventy-eight patients (64%) had T2 lesions, while an additional 27 patients (22.3%) met the expanded UCSF criteria, termed T3A lesions. The rest 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.
 
In summary, interpretation of the data for all indications for TACE as a bridge to transplant is extremely limited, due to the heterogeneous groups of patients given a variety of loco-regional therapies. Protocols vary among institutions, and often how the type of loco-regional therapy is selected is not provided.
 
2007 - 2008 Update
The policy was updated with a literature review using MEDLINE search conducted in January 2008.
 
TACE for unresectable HCC
Biselli reported on 56 cirrhotic patients with unresectable HCC undergoing at least 1 course of TACE who were matched 1:1 for sex, age (in 5-year periods), parameters of Child-Pugh score, Okuda stage, and tumor type with a control group who had received only supportive care.  The 2 groups were comparable for cause of cirrhosis, alpha-fetoprotein serum levels, and Cancer of the Liver Italian Program (CLIP) score. The 56 patients in the TACE group received a total of 123 treatment courses. Survival rates at 12, 24, and 30 months in patients receiving TACE were 74.3%, 52.1%, and 38.8%, respectively, with a median survival time of 25 months, whereas in supportive care patients the rates were 39.4%, 25.4%, and 19%, respectively, with a median survival time of 7 months (P = .0004). At univariate analysis, TACE, tumor type, presence of ascites, alpha-fetoprotein serum level, CLIP score, and Okuda stage were associated significantly with survival. Only TACE and CLIP score proved to be independent predictors of survival at multivariate analysis. In a prospective study from a single center in Canada, Molinari reported on the effectiveness of TACE for HCC in a North American population.  Child-Pugh A cirrhosis or better patients with unresectable HCC and without radiological evidence of metastatic disease or segmental portal vein thrombosis were assessed between November 2001 and May 2004. Of 54 patients who satisfied the inclusion criteria, 47 underwent 80 TACE sessions. Chemoembolization was carried out using doxorubicin and lipiodol followed by an injection of embolic particles when necessary. Repeat treatments were carried out at 2-3 month intervals for recurrent disease. The survival probabilities at 1, 2 and 3 years were 76.6, 55.5 and 50%, respectively. At 6 months after the first intervention, 31% of patients had a partial response and 60% had stable disease. Major adverse events occurred after 20% of sessions, including 2 treatment-related deaths (4% of patients). The authors concluded that these survival probabilities at 1 and 2 years after TACE were comparable with results in randomized studies from Europe and Asia. Takayasu reported results from an 8-year prospective cohort study of TACE from Japan.  In this study, 8510 patients with unresectable HCC underwent TACE using emulsion of lipiodol and anticancer agents followed by gelatin sponge particles as an initial treatment. Exclusion criteria were extrahepatic metastases and/or any previous treatment prior to the present TACE. The mean follow-up period was 1.77 years. For overall survival rates by TACE, median and 1-, 3-, and 5-year survivals were 34 months, 82%, 47%, and 26%, respectively. The multivariate analyses showed significant difference in degree of liver damage (P = .0001), alpha-fetoprotein value (P = .0001), maximum tumor size (P = .0001), number of lesions (P = .0001), and portal vein invasion (P = .0001). The TACE-related mortality rate after the initial therapy was 0.5%.
 
Taken in their totality, the recent studies of TACE for patients with unresectable HCC confined to the liver who meet specific selection criteria (i.e., good hepatic function/reserve and no portal vein thrombosis) consistently demonstrate improved survival compared to only supportive care. In addition, there is a high level of consistency among recent controlled trials and the large cohort study described above in the 2008 update. In addition, the studies show a relatively low complication rate for carefully selected patients in these research settings. Thus, TACE can be considered an option for a patient with unresectable hepatocellular cancer who has good hepatic function and does not have portal vein thrombosis. However, studies are lacking that demonstrate which of the potential treatments (for example, radiofrequency ablation) might be preferred in a given patient.
 
TACE for hepatic metastases from neuroendocrine tumors
Ruutiainen reported on a study of 67 patients comparing bland embolization to TACE in neuroendocrine tumors metatstatic to the liver.  In this study, 67 patients underwent 219 embolization procedures: 23 patients received primarily bland embolization with PVA with or without iodized oil and 44 primarily received chemoembolization with cisplatin, doxorubicin, mitomycin-C, iodized oil, and polyvinyl alcohol. Patients with disease relapse were treated again when feasible. Ten of 67 patients (15%) were lost to follow-up. Toxicities of grade 3 or worse in severity occurred after 25% of chemoembolization procedures and 22% of bland embolization procedures. Rates of freedom from progression at 1, 2, and 3 years were 49%, 49%, and 35% after chemoembolization and 0%, 0%, and 0% after bland embolization (log-rank test, P = .16). Patients treated with chemoembolization and bland embolization experienced symptomatic relief for means of 15 and 7.5 months, respectively (P = 0.14). Survival rates at 1, 3, and 5 years after therapy were 86%, 67%, and 50%, respectively, after chemoembolization and 68%, 46%, and 33%, respectively, after bland embolization (P = .18). The authors concluded that chemoembolization demonstrated trends toward improvement in TTP (time to progression), symptom control, and survival and indicated that a multicenter prospective randomized trial is warranted. These results are similar to those reported previously by Gupta who noted that in a retrospective series of 81 patients, hepatic artery embolization or chemoembolization results in symptomatic and radiographic response in most patients with carcinoid metastases to the liver.  Osborne reported on a nonrandomized study of 59 patients with neuroendocrine tumors who received either cytoreduction or embolization for symptomatic hepatic metastases. The duration of symptom relief (35 vs. 22 months) and survival (43 vs. 24 months) both favored the cytoreduction approach. The authors comment that cytoreduction should be pursued when possible even if complete resection may not be achievable. Thus, for patients with metastatic neuroendocrine tumors whose symptoms persist despite systemic therapy and who are not candidates for resection, transcatheter arterial chemoembolization is one option that can be used for symptomatic treatment. The policy statements are revised for this indication.
 
Uveal Melanoma Metastatic to Liver
Uveal (ocular) melanoma is an uncommon malignancy. However, unlike most cutaneous melanomas, metastatic uveal melanoma is frequently confined to the liver. The most recent study describing the use of TACE in the treatment of melanoma metastatic to the liver was reported in a series of 20 patients (17 with ocular melanoma) treated between 2004 and 2007 as described by Sharma, et al.  The 20 patients underwent 46 TACE sessions (mean, 2.4 sessions; range, 1-5). The mean and median overall survival times were 334 and 271 days, respectively. There were no deaths within 30 days of treatment. The authors noted that this treatment resulted in longer survival than has been noted among historical controls. This work builds on results reported by Bediken in 1995 that showed that TACE had a 36% response rate (cisplatin chemoembolization) compared to a 1% response rate to systemic chemotherapy.  Patel reported on BCNU treatment for uveal melanoma and demonstrated that those who responded had improved survival. (38) In this study, 18 of the 24 patients experienced regression or stabilization of hepatic metastases for at least 6 weeks. The overall response rates (complete and partial responses) for intention-to-treat patients and for patients who were evaluable for response were 16.7 and 20.4%, respectively. The median overall survival of the entire intention-to-treat group of patients was 5.2 months, for patients with complete or partial response in hepatic metastases 21.9 months, for patients with stable disease 8.7 months, and for patients with progressive disease 3.3 months. Thus, for patients with metastatic uveal melanoma who have disease confined to the liver, the metastatic liver disease may respond to TACE treatment and patients who respond to TACE have improved survival.
 
TACE as a Technique to Prevent Tumor Progression While on the Waiting List
TACE continues to be utilized in various roles in patients with hepatocellular cancer who are being considered for liver transplantation. Many of the studies are in patients who meet accepted criteria for liver transplantation and for whom TACE (or other modalities such as radiofrequency ablation and embolization) are used to prevent tumor progression while awaiting liver transplantation. Obed and colleagues reported on 20 patients with non-progression of lesions after TACE who had liver transplantation; median survival in this group was 92.3 months.  Thus, given these data, the data presented above, and the accepted role within the transplant community of using TACE to maintain size criteria, this indication is covered. The candidate for TACE to maintain tumor size pre-transplantation should have a single tumor less than 5cm or no more than 3 tumors each less than 3 cm in size, absence of extrahepatic disease or vascular invasion, and Child-Pugh score of either A or B.
 
The literature search did not identify any comparative trials that address the other clinical applications of TACE for those with liver malignancies (primary or metastatic).
 
2010 Update
 
TACE for resectable hepatocellular carcinoma (HCC) - (TACE as neoadjuvant or adjuvant therapy)
 
Preoperative TACE
In 2009, Chua and colleagues conducted a systematic review of neoadjuvant transarterial chemoembolization for resectable hepatocellular carcinoma (Chua, 2009).  They evaluated 18 studies, including 3 randomized trials and 15 observational studies, some of which are outlined in detail in the following section. The review was comprised of 3,927 patients, of which 1,293 underwent neoadjuvant TACE. The conclusions were that TACE could be used safely and resulted in high rates of pathologic responses, but did not appear to improve disease-free survival in the TACE group. No conclusions could be drawn with respect to overall survival differences between the TACE and non-TACE groups due to the heterogeneity of the results across studies.
 
From July 2001 to December 2003, Zhou and colleagues randomized 108 patients with resectable HCC (≥5 cm suitable for a partial hepatectomy) to preoperative TACE treatment (n=52) or no preoperative treatment (control group) (n=56) (Zhou, 2009).   Five patients (9.6%) in the preoperative TACE group did not receive surgical therapy because of extrahepatic metastasis or liver failure. The preoperative TACE group had a lower resection rate (n=47, 90.4% vs. n=56, 100%; p=0.017), and longer operative time (mean: 176.5 minutes vs. 149.3 minutes; p=0.042). No significant difference was found between the 2 groups in mortality. At a median follow-up of 57 months, 41 (78.8%) of 52 patients in the preoperative TACE group and 51 (91.1%) of 56 patients in the control group had recurrent disease (p=0.087). The 1-, 3-, and 5-year disease-free survival rates were 48.9%, 25.5%, and 12.8%, respectively, for the preoperative TACE group and 39.2%, 21.4%, and 8.9%, respectively, for the control group (p=0.372). The 1-, 3-, and 5-year overall survival rates were 73.1%, 40.4%, and 30.7%, respectively, for the preoperative TACE group and 69.6%, 32.1%, and 21.1%, respectively, for the control group (p=0.679). Preoperative TACE did not improve surgical outcome, and it resulted in drop-out from definitive surgery because of progression of disease and liver failure.
 
Zhang et al. retrospectively analyzed the therapeutic results of 1457 HCC patients treated with hepatectomy, 120 of whom had received TACE before surgical resection (Zhang, 2000).   They showed that the 5-year disease-free survival rates of the patients who received more than 2 sessions of TACE, those who received one session of TACE, and no TACE patients were 51.0%, 35.5%, and 21.4%, respectively, and that the mean disease-free survival times of the 3 groups were 66.4, 22.5 and 12.5 months, respectively. They concluded that effective preoperative TACE may be one of the best methods that can be clinically performed at present, for resectable HCC, including small HCC, for improving disease-free survival after hepatectomy. On the other hand Choi et al. studied 273 patients who underwent curative resection for HCC; 120 of them underwent preoperative TACE. The 1-, 3-, and 5-year disease-free survival rates were 76.0%, 57.7%, and 51.3%, respectively, in the TACE group and 70.9%, 53.8%, and 46.8%, respectively, in the non-TACE group. Although a difference was noted between the TACE and non-TACE groups, it was not significant (Choi, 2007).
 
Postoperative TACE
Li and colleagues described the results of their randomized study exploring the efficacy of postoperative TACE and portal vein chemotherapy (PVC) for patients with HCC complicated by portal vein tumor thrombosis (PVTT) and to evaluate prognostic factors (Li, 2006).  The study cohort consisted of 112 patients with HCC and PVTT randomly divided into three groups: Group A (37 patients), surgery only; Group B (35 patients), operation plus TACE; Group C (40 patients), operation plus TACE and PVC. Portal vein thrombus extirpation was performed at the time of surgery. Adverse effects and complications were mostly related to the operation, catheters, and local chemotherapy and included liver decompensation (15.0%), catheter obstruction (11.6%), and nausea and loss of appetite (22.1%). The disease-free survival curve was significantly different among the 3 groups, as estimated by the Kaplan-Meier method (both p<0.05). Group C showed a higher disease-free survival rate than Group A (p<0.05), but no statistical differences were found between group A and group B, or group B and group C (both p >0.05). The 1–3, and 5-year disease-free survival rates in Group A (resection only, n=37) were 50.7, 17.8, and 0%, respectively; in Group B (resection + TACE, n=35), rates were 62.3, 23.7, and 4.0%, respectively, and in Group C (resection + TACE + PVC, n=40) increased to 74.4, 46.1, and 11.5%, respectively. Tumor size, tumor number, PVTT location, and treatment modalities were independent prognostic factors (p<0.05). The authors concluded that postoperative TACE combined with PVC may benefit the survival of patients with HCC complicated by PVTT in the short-term (less than 60 months), but long-term efficacy is not yet certain and needs to be confirmed by further studies.
 
TACE as a bridge to liver transplant
 
TACE has been explored in various settings: as a technique to prevent tumor progression in patients on the liver transplant 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. All of these indications are in part related to the UNOS liver allocation policy, which prioritizes patients for receiving donor livers. The UNOS policy and the above 3 indications are discussed further in the following sections.
 
UNOS Liver Allocation Policy
 
In 2002, UNOS introduced a new liver allocation system, model for endstage liver disease (referred to as MELD) for adult patients awaiting liver transplant. 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 6 (less ill) to 40 (gravely ill). Aside from those in fulminant liver failure, donor livers are prioritized to those with the highest MELD number. This scale accurately 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: 1 nodule 1.9 cm or smaller
 
T2: 1 nodule between 2.0 and 5.0 cm, or 2 or 3 nodules each smaller than 3.0 cm
 
T3: 1 nodule larger than 5.0 cm, or 2 or 3 nodules with at least 1 larger than 3.0 cm
 
In considering how to allocate the scarce donor organs, UNOS sought to balance risk of death on the waiting list against risk of recurrence after transplant. Patients with T1 lesions were 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 to those 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). Note that 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 strong incentives to use locoregional therapies to downsize tumors to T2 status and to prevent progression while on the waiting list. A 2010 report of a national conference on liver allocation in patients with hepatocellular carcinoma in the U.S. addressed the need to better characterize the long-term outcomes of liver transplantation for patients with HCC and to assess whether it is justified to continue the policy of assigning increased priority for candidates with early stage HCC on the transplant waiting list in the U.S (Pomfret, 2010).  At the completion of the meeting, there was a general consensus for the development of a calculated continuous HCC priority score for ranking HCC candidates on the list that would incorporate the calculated MELD score, alpha-fetoprotein, tumor size, and rate of tumor growth and that only candidates with at least stage T2 tumors would receive additional HCC priority points. The report addressed the role of locoregional therapy to downstage patients from T3 to T2, and stated that the results of downstaging before liver transplantation are heterogeneous, with no upper limits for tumor size and number before downstaging across studies, and the use of different endpoints for downstaging before transplantation.
 
TACE as a Technique to Prevent Tumor Progression While on the Waiting List
 
Several studies have reported dropout rates of wait-listed patients treated with locoregional therapy. However, lacking controlled data, it is difficult to assess contributions of locoregional therapy to time on the waiting list. In addition, in 2002, as discussed here, UNOS revised its liver allocation policy, such that 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 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 (Graziadei, 2003).  None was removed from the list due to tumor progression, and mean waiting time was 178 (+/- 105) days. Maddala and colleagues studied the dropout rates of 54 patients receiving TACE while awaiting transplantation (Maddala, 2004).  During a median waiting time of 211 days (range: 28–1,099 days), the dropout rate was 15%. More recently, Fisher and colleagues 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 (Fisher, 2004).   In this protocol, patients with tumors larger than 5 cm were not considered transplant candidates until the tumor was completely ablated using TACE, radiofrequency ablation (RFA), or another technique. Yamashiki and colleagues 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 larger than 3 cm affected the dropout rate due to tumor progression (Yamashiki, 2005).
 
TACE to Downstage HCC Prior to Transplant/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 (Pomfret, 2010).  Some patients with T3 lesions apparently are cured with liver transplant, although most experience recurrent tumor. For example, in the seminal 1996 study (Mazzaferro, 1996), the 4-year recurrence-free survival was 92% in those who met the “Milan criteria” (T2 lesion) 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 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 smaller or no more than 3 lesions with none greater than 3 cm and with a sum of tumor diameters 8 cm or smaller. These expanded criteria are known as “the UCSF criteria.” (Merli, 2005)
 
Lewandowski and colleagues compared radioembolization with chemoembolization in the efficacy of downstaging 86 patients with HCC from stage T3 to T2 (Lewandowski, 2009).  Patients were treated with either 90-yttrium microspheres (n=43) or TACE (n=43). Median tumor size was similar between the two treatment groups (5.7 and 5.6 cm, for TACE vs. radioembolization, respectively.) Partial response rates were 61% versus 37% for radioembolization vs. TACE, respectively with downstaging from T3 to T2 in 58% of patients treated with radioembolization versus 31% with TACE (p<0.05).
 
The results and efficacy of downstaging with TACE to achieve a reduction in tumor burden to a T2 lesion remain controversial. There are retrospective data showing the ability to downstage patients with TACE, however, there is no randomized evidence that tumor downstaging prior to liver transplant confers a survival advantage.
 
TACE for hepatic metastases from colorectal cancer
 
For patients with liver metastases from colorectal cancer that do not qualify for surgical resection, traditionally, systemic chemotherapy is first-line treatment. However, in more than 60% of cases, the treatment fails and disease progresses. For the large proportion of patients in whom second- and third-line medical treatment has failed, other palliative therapies to control disease progression and symptoms have been studied, include TACE (Hong, 2009).
 
The literature has reported a median survival in patients with liver-dominant colorectal metastases treated with chemoembolization from 7–23 months (Stuart, 1995) (Lang, 1993).  However, studies are difficult to compare, as some patients who were treated were still eligible for systemic chemotherapy, and survival was sometimes calculated and reported as a mean time from the date of diagnosis of liver metastases rather than from the first treatment with TACE.
 
Vogl and colleagues evaluated tumor control and survival in 463 patients with unresectable liver metastases of colorectal origin that did not respond to systemic chemotherapy and were treated with TACE (Vogl, 2009).  Of the 463 patients, 67% had 5 or more metastases, 8% had 1 metastasis, 10% had 2, and 14% had 3 or 4. Patients were treated at 4-week intervals, with a total of 2,441 chemoembolization procedures performed (mean, 5.3 sessions per patient), using one of three local chemotherapy protocols. Local tumor control was partial response in 68 patients (14.7%), stable disease in 223 patients (48.2%), and progressive disease in 172 patients (37.1%). Median survival from the start of TACE treatments was 14 months (compared to the results from a previous study by the same author, in which untreated patients had a survival rate of 7–8 months). (36) One-year survival rate after TACE was 62% and 28% at 2 years. No difference in survival was observed between the three different local chemotherapy protocols.
 
Hong and colleagues compared salvage therapy for liver-dominant colorectal metastatic adenocarcinoma using TACE or 90-yttrium radioembolization (Hong, 2009).   Mean dominant lesion sizes were 9.3 cm and 8.2 cm in the chemoembolization and radioembolization groups, respectively. Multilobar disease was present in 67% and 87% of the respective groups, and extrahepatic metastases were present in 43% and 33%, respectively. Of 36 patients, 21 underwent TACE, with a median survival of 7.7 months (survival measured from the date of the first TACE treatment to the date of death or to April 2007, if still living). Survival results were comparable to other studies addressing colorectal cancer and TACE, which ranged from 7–10 months. Median survival was 6.9 months for the radioembolization group (p=0.27). The 1-, 2-, and 5-year survival rates for the two groups were 43%, 10%, and 0%, respectively, for the chemoembolization group and 34%, 18%, and 0%, respectively, for the radioembolization group.
 
TACE for hepatic metastases from breast cancer
 
Vogl and colleagues reported the efficacy of repeated treatments with TACE in 208 patients with unresectable hepatic metastases from breast cancer (Vogl, 2010).   A total of 1,068 chemoembolizations were performed (mean 5.1 sessions per patient, range: 3-25). Mean patient age was 56.4 years (range: 29-81). Patients received either one of two chemotherapeutic agents alone (mitomycin-C or gemcitabine) or in combination. Tumor response was evaluated by MRI according to RECIST criteria. For all chemotherapy protocols, local tumor control was partial response 13% (27/208), stable disease 50.5% (105/208), and progressive disease 36.5% (76/208). The 1-, 2-, and 3-year survival rates after TACE were 69, 40, and 33%. Median and mean survival times from the beginning of the TACE sessions were 18.5 and 30.7 months. Treatment with mitomycin-C only showed median and mean survival times of 13.3 and 24 months, and with gemcitabine only 11 and 22.3 months. With a combination of mitomycin-C and gemcitabine median and mean survival were 24.8 and 35.5 months.
 
2010 National Comprehensive Cancer Network (NCCN) guidelines  
 
Hepatocellular carcinoma (v.2.2010): chemoembolization is listed as an embolization option for patients with unresectable hepatocellular carcinoma with tumors not amenable to ablation therapy only and in the absence of extrahepatic disease [category 2A] with the additional recommendation that tumor lesions larger than 5 cm should be treated using arterial embolic approaches, whereas those tumors 3-5 cm can be considered for combination therapy with ablation and arterial embolization.
 
Neuroendocrine tumors, carcinoid and islet cell tumors (v.2.2010): chemoembolization is recommended for patients with unresectable, liver-dominant metastases [category 2B].
 
Colon cancer (v.1.2011): NCCN guidelines state the use of intra-arterial embolization for metastatic colon cancer to the liver “is a category 3 recommendation based on limited evidence and different institutional practice patterns”.
 
No NCCN guidelines were identified for ocular malignancies.
 
Breast cancer (v2.2010): TACE is not addressed as a treatment option for breast cancer metastatic to the liver.
 
2012 Update
Mabed et al. (2009) published the results of a randomized controlled trial of transcatheter arterial chemoembolization (TACE) with lipiodol, doxorubicin and cisplatin versus intravenous doxorubicin for patients with unresectable hepatocellular carcinoma. A total of 100 patients with unresectable HCC were recruited and randomized to be treated with either (TACE) or systemic chemotherapy. Fifty patients were treated with TACE using lipiodol, doxorubicin and cisplatin, while 50 patients were treated with systemic doxorubicin alone. Patients treated with TACE achieved a significantly higher response rate, with partial response achieved in 16 patients (32%) versus five patients (10%) in the chemotherapy arm (P = 0.007). A significantly more favorable tumor response to chemoembolization was found in patients with single lesions (P = 0.02), Child class A (P = 0.007), Okuda stage 1 (P = 0.005) and alpha-feto protein less than 400 ng/mL (P < 0.001). The probability of tumor progression was significantly lower in cases treated with TACE where the median progression free survival was 32 weeks (range, 16-70 weeks) versus 26 weeks (range, 14-54 weeks) for patients treated with systemic chemotherapy (P = 0.03). However, the median overall survival did not differ significantly in cases treated with TACE (38 weeks) compared with those treated with chemotherapy (32 weeks) (P = 0.08), except for patients with serum albumin >3.3 g/dL (60 vs. 36 weeks; P = 0.003). Multivariate Cox regression analysis showed that a rise of serum albumin by 1 g/dL is associated with a decrease in the risk of death by 33% (95% confidence interval: 0.12-0.94, P = 0.038). Mortality in the chemoembolization arm was due to tumor progression in 18 patients (53%), liver failure in 11 patients (32%) and gastro intestinal tract (GIT) bleeding in 5 patients (15%). Mortality in the chemotherapy arm was due to tumor progression in 23 patients (64%), liver failure in 9 patients (25%) and GIT bleeding in 4 patients (11%). Treatment-related mortality was 4% in the TACE arm versus 0% in the chemotherapy arm. In conclusion, the overall survival benefits of TACE and systemic doxorubicin are similar for patients with unresectable HCC amenable to either treatment. It is crucial to optimize the benefit-risk ratio of TACE. In this setting, serum albumin level is a candidate marker for selection of cases who may benefit from this procedure.
 
2011 National Comprehensive Cancer Network (NCCN) Guidelines
    • Hepatocellular carcinoma (v.2.2011): chemoembolization is listed as an option for patients with unresectable hepatocellular carcinoma with tumors not amenable to ablation therapy only and in the absence of large volume extrahepatic disease [category 2A] with the additional recommendation that tumor lesions larger than 5 cm should be treated using arterial embolic approaches, whereas those tumors 3-5 cm can be considered for combination therapy with ablation and arterial embolization.
    • Intrahepatic cholangiocarcinoma (v.1.2011): does not address the use of TACE in intrahepatic cholangiocarcinoma.
    • Neuroendocrine tumors, carcinoid, and islet cell tumors (v.2.2011): chemoembolization is recommended for patients with unresectable liver metastases [category 2B].
    • Colon cancer (v.3.2011): the use of arterially-directed embolic therapy for metastatic colon cancer to the liver has a category 3 recommendation (based upon any level of evidence, there is major NCCN disagreement about whether the intervention is appropriate).
    • No NCCN guidelines were identified for ocular malignancies.
    • Breast cancer (v2.2011): TACE is not addressed as a treatment option for breast cancer metastatic to the liver.
 
National Cancer Institute Clinical Trials
A Phase III trial is recruiting patients with unresectable HCC to be randomized to TACE with versus without sorafenib. (NCT01004978) Primary outcome measure is progression-free survival, with secondary outcome measures including overall survival, anatomic patterns of failure, toxicity and tumor response. Estimated enrollment is 400, with estimated trial completion date September 2012.
A Phase III trial is recruiting patients with HCC with one lesion 5 cm or larger or multinodular disease with 4 or more lesions (at least one larger than 3 cm) to receive TACE with or without brivanib as adjuvant treatment. (NCT00908752) Estimated enrollment is 870 and estimated study completion date is March 2015.
A Phase III trial is recruiting patients with recurrent HCC to be randomized to TACE or Cyberknife stereotactic body radiotherapy. (NCT01327521) Outcome measures include efficacy, toxicity, and progression-free and overall survival. Estimated enrollment is 120 with an estimated study completion date of February 2016.
 
Summary
Studies (including randomized trials) of TACE for patients with unresectable HCC confined to the liver who meet specific selection criteria have shown improved survival compared to only supportive care.  There are little data on the use of TACE in the neoadjuvant or adjuvant setting, and a significant long-term survival benefit has not been demonstrated in patients with resectable HCC.  TACE has become an accepted method to prevent tumor growth while patients are on the liver transplant wait list.
For metastatic neuroendocrine tumors, studies have included heterogeneous patient populations, and interpretation of survival data using TACE is difficult. Several studies have shown reduced tumor burden, reduced hormone levels, and palliation of symptoms with TACE. In patients with metastatic colorectal cancer and other metastases, studies have consisted of small numbers of patients, and the results have been variable across studies due to variation in patient selection criteria and regimens used between different studies. At this time, the data do not support the use of TACE in these settings.
 
2013 Update
A literature search was conducted using the MEDLINE database through September 2013. There was no new randomized controlled trials or other published literature that would prompt a change in the coverage statement. The following is a summary of the key identified literature.
 
In 2013, Zhou et al. reported on a meta-analysis of 21 studies evaluating preoperative TACE (Zhou, 2013). Included in the studies were 4 were randomized controlled trials and 17 nonrandomized studies with a total of 3,210 patients. Preoperative TACE was given to 1,431 patients with the remaining 1,779 serving as controls. In 18 studies, 5-year disease-free survival for preoperative TACE ranged from 7.0–57% and 8.0–48.8% in the controls. In 16 studies, the 5-year overall survival for preoperative TACE was 15.4–62.7% and 19.0–62.5% in the controls. In the pooled analyses, there were no significant improvements with preoperative TACE versus controls in 5-year disease-free (32.1% vs. 30.0%, p=0.17) and overall survival (40.2% vs. 45.2%, p=0.37). Intra- and extra-hepatic recurrence were also not significantly different in the pooled analyses (51.2% vs.53.6% and 12.9% vs.10.3%, p=0.19, respectively).
 
Richardson and colleagues reported on a systematic review of 1 RCT and 5 observational studies on TACE with irinotecan-eluting beads for unresectable colorectal liver metastasis (Richardson, 2013). Survival times ranged from a median of 15.2 months to 25 months. The most common adverse event was post- embolization syndrome (abdominal pain, nausea, and vomiting) followed by hypertension. In the RCT included in the Richardson systematic review, Fiorentini et al. reported on 74 patients randomly allocated to TACE with irinotecan-eluting beads (n=36) or systemic irinotecan, fluorouracil and leucovorin (n=38) (Fiorentini, 2012). With irinotecan-eluting beads, overall survival was significantly longer with a median overall survival of 22 months (95% CI: 21-23 months) versus 15 months (95% CI: 12-18) for the systemic chemotherapy group (p=0.031). Progression-free survival was significantly longer at 7 months (95% CI: 3-11) in the irinotecan-eluting beads group compared to 4 months (95% CI: 3-5) months in the systemic chemotherapy group (p=0.006). However, larger studies are needed to confirm these findings.
 
2014 Update
A literature search conducted through September 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
In 2014 Boehm et al reported on a meta-analysis of 20 studies (N=657) on the hepatic artery therapies of
TACE, hepatic artery infusion and Yttrium(90) for ICC (Boehm, 2014). The median overall survival was lowest for TACE and drug-eluting bead TACE (12.4 and 12.3 months, respectively) when compared to hepatic artery infusion (22.8 months) and Yttrium(90) (13.9 months). Complete and partial response to therapy was also lowest with TACE (17.3%) compared to Yttrium(90) (27.4%) and hepatic artery infusion (56.9%). However, TACE had less Grade III/IV toxicity than hepatic artery infusion (0.26 vs. 0.35 events per patient, respectively).
 
2015 Update
A literature search conducted through September 2015 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
A 2015 retrospective cohort study by Yeh and colleagues investigated whether TACE plus sequential curative therapy provided a survival benefit in patients with a single hepatocellular carcinoma (HCC) compared to curative surgery, radiofrequency ablation or percutaneous ethanol injection (Yeh, 2015).  A total of 470 patients with a diagnosis of single HCC between 2005 and 2010 were included. The 1-, 3-, and 5-year OS rates of all patients were 93%, 73%, and 60%, respectively. Child-Pugh class A (HR=2.04; 95% CI, 1.277 to 3.254; p=0.003), very early stage Barcelona Clinic Liver Cancer (BCLC; HR=2.03; 95% CI, 1.021 to 4.025; p=0.043), tumor size less than 5 cm (HR=1.75; 95% CI, 1.115 to 2.751; p=0.015), alpha fetoprotein (AFP) level less than 200 ng/mL (HR=2.07; 95% CI, 1.346 to 3.182; p=0.001), and curative-based therapy (HR=2.16; 95% CI, 1.442 to 3.224; p<0.001) were factors associated with better OS. The 1-, 3-, and 5-year disease-free survival (DFS) rates of all the patients were 75%, 54%, and 36%, respectively. Only Child-Pugh class A (HR=1.57; 95% CI, 1.068 to 2.294; p=0.022) and curative-based therapy (HR=1.51; 95% CI, 1.128 to 2.028; p=0.006) were significantly associated with better DFS. Neoadjuvant TACE did not provide benefit compared with curative therapy alone in subgroup analysis.
 
Unresectable Hepatocellular Carcinoma
The evidence on TACE for individuals who have unresectable hepatocellular carcinoma (HCC) confined to the liver and who meet specific selection criteria (ie, good hepatic function/reserve and no portal vein thrombosis) includes several RCTs, large observational studies, and systematic reviews. Relevant outcomes are overall survival, disease-specific survival, quality of life, treatment-related mortality and morbidity. Overall, studies have shown improved OS compared with only supportive care. One systematic review highlighted some of the possible biases associated with these studies. The evidence is sufficient to determine quantitatively that the technology results in a meaningful improvement in the net health outcome.
 
TACE in the Liver Transplant Setting for HCC
The evidence on TACE for individuals who have unresectable hepatocellular carcinoma (HCC) confined to the liver and, who meet specific selection criteria for liver transplantation, includes many observational studies. Relevant outcomes are overall survival, disease-specific survival, quality of life, treatment-related mortality and morbidity. TACE has become an accepted method to prevent tumor growth and progression while patients are on the liver transplant wait list. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.
 
Symptomatic Unresectable Metastatic Neuroendocrine Tumors
The evidence on TACE for patients who have unresectable metastatic neuroendocrine tumors includes observational studies and reviews. Relevant outcomes are overall survival, disease-specific survival, quality of life, treatment-related mortality and morbidity. Several studies have shown reduced tumor burden, reduced hormone levels, and palliation of symptoms with TACE. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.
 
Hepatic Metastases from Uveal Melanoma
The evidence on TACE for patients who have unresectable metastatic uveal melanomas includes observational studies and reviews. Relevant outcomes are overall survival, disease-specific survival, quality of life, treatment-related mortality and morbidity. Several studies have shown a survival advantage using locoregional treatment modalities, including TACE, in patients who have liver-dominant metastases from ocular melanoma. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.
 
Neoadjuvant or Adjuvant TACE in Patients with Resectable HCC
The evidence on TACE in the neoadjuvant or adjuvant setting in patients who have resectable HCC includes several RCTs and systematic reviews. Relevant outcomes are overall survival, disease-specific survival, quality of life, treatment-related mortality and morbidity. Overall, studies have shown little to no difference in OS rates with neoadjuvant or adjuvant TACE compared with surgery alone. A meta-analysis found no significant improvements in survival or recurrence with the use of preoperative TACE for resectable HCC. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
Unresectable Cholangiocarcinoma
The evidence on TACE for patients who have unresectable cholangiocarcinoma includes several retrospective observational studies and systematic reviews. Relevant outcomes are overall survival, disease-specific survival, quality of life, treatment-related mortality and morbidity. Most of the data on TACE is for unresectable intrahepatic cholangiocarcinoma. Although the data suggest an OS advantage with TACE versus supportive care or systemic chemotherapy alone, the data consist mostly of retrospective reviews without matched patient controls. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
Other Hepatic Metastatic Lesions
The evidence on TACE for patients who have unresectable, intrahepatic metastatic tumors (eg, colorectal or breast cancer) includes RCTs, numerous observational studies, and systematic reviews. Relevant outcomes are overall survival, disease-specific survival, quality of life, treatment-related mortality and morbidity. Studies have consisted of small numbers of patients, and the results have been variable across studies due to variation in patient selection criteria and regimens used between different studies. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
Recurrent Hepatic Cancer
The evidence on TACE for patients who have recurrent HCC includes few cases typically reported within observational series; no comparative evidence is available on the use of TACE to treat HCC recurrence. Relevant outcomes are overall survival, disease-specific survival, quality of life, treatment-related mortality and morbidity. Studies have included small numbers of patients, and the results have been variable across studies due to variation in patient selection criteria and regimens used between different studies. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
2016 Update
 
A literature search was conducted using the MEDLINE database. There was no new literature identified that would prompt a change in the coverage statement. One new randomized controlled trial was identified. Bush et al published interim results of an RCT comparing TACE to proton beam radiotherapy for patients with unresectable HCC (Bush, 2016). This trial included 69 patients, with 36 randomized to TACE and 33 to proton beam. The primary outcome was progression-free survival (PFS) at 2 years and secondary outcomes were OS, local tumor control, and days of hospitalization following treatment. There was a trend toward worse PFS at 2 years in the TACE group (31%) compared to the proton beam group (48%; p=0.06). The total days of hospitalization in the 30 days posttreatment was significantly lower for the TACE group (24 days vs 166 days, p<0.01). For the outcome of local tumor control, there was a trend toward worse control in the TACE group (45% vs 88%, p=0.06), and there was no difference between groups in OS.
 
Systematic Reviews
Two systematic reviews focused on comparing TACE with hepatic resection, and concluded that hepatic resection is superior to TACE for eligible patients (Qi, 2015; Tian, 2015).
 
Zacharias et al published a meta-analysis on hepatic artery based therapies for colorectal metastases (Zacharias, 2015). Techniques included TACE, HAI chemotherapy, and radioembolization. Ninety studies reported on outcomes of HAI-based therapy. Eight studies were RCTs, including 1 RCT of TACE. On combined analysis, OS for patients treated with TACE was 15.2 months, compared to 21.4 months with HAI and 29.4 months with radioembolization. Differences between groups were not statistically significant. Grade 3 or 4 toxicity was 40% in the HAI group, 19% in the radioembolization group, and 18% in the TACE group.
 
2017 Update
A literature search conducted using the MEDLINE database did not reveal any new information that would prompt a change in the coverage statement.
 
 

CPT/HCPCS:
37243Vascular embolization or occlusion, inclusive of all radiological supervision and interpretation, intraprocedural roadmapping, and imaging guidance necessary to complete the intervention; for tumors, organ ischemia, or infarction
75894Transcatheter therapy, embolization, any method, radiological supervision and interpretation

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A Randomized, Double-blind, Multicenter Phase III Study of Brivanib Versus Placebo as Adjuvant Therapy to Trans-Arterial Chemo-Embolization (TACE) in Patients With Unresectable Hepatocellular Carcinoma (The BRISK TA Study). www.clinicaltrial.gov - NCT00908752; last accessed 10/18/2012.

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