BlueCross and BlueShield of Montana Medical Policy/Codes
Transcatheter Arterial Embolization for Cancer Treatment
Chapter: Medicine: Treatments
Current Effective Date: March 01, 2010
Original Effective Date: May 01, 2006
Publish Date: March 01, 2010
Revised Dates: January 2, 2008, November 7, 2008, March 1, 2010
Description

Transcatheter arterial chemoemobolization (TACE) has been investigated to treat resectable, unresectable, and recurrent hepatocellular carcinoma and to treat liver metastases most commonly from colorectal cancer. Chemoembolization requires hospitalization for placement of a hepatic artery catheter via the femoral artery through which a viscous material containing one or more antineoplastic agents is injected. "Bland embolization" is embolization without chemotherapy. Radioactive isotopes may also be included in the material injected for localized radiotherapy. This is covered in the medical policy: "Selective Internal Radiation Therapy for Primary and Metastatic Tumors of the Liver."

The rationale for TACE is that it delivers effective local doses, while possibly minimizing systemic toxicities associated with oral or intravenous chemotherapy. Also, the viscous material and the chemotherapy may exert synergistic effects (cytotoxicity from the chemotherapy, potentiated by anoxia in the infarcted region). Typically, only one lobe of the liver is treated during a single session, with subsequent embolization procedures scheduled from five days to six weeks later. In addition, since the embolized vessel recanalizes, chemoembolization can be repeated as many times as necessary.

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 can still be highly variable, which raises questions regarding the validity of the results.

The preponderance of evidence based on randomized, prospective, controlled clinical trials does not support the conclusion that chemoembolization improves survival in hepatocellular carcinoma. No randomized, prospective, controlled clinical trials have been preformed to assess survival benefit in patients with hepatic metastasis.

Treatment alternatives include resection when possible and chemotherapy administered systemically or by hepatic artery infusion, which involves continuous infusion of chemotherapy with an implanted pump and does not use embolic material.

Policy

Medically Necessary

Blue Cross and Blue Shield of Montana (BCBSMT) considers the following use of transcatheter hepatic arterial embolization (TACE) medically necessary:

  • Bridge to liver transplant.* This is recognized by the United Network for Organ Sharin (UNOS) allocation system for donor livers as a component of patient management during the waiting period for a donor liver. See policy guidelines.
  • To treat hepatocellular cancer that is unresectable but confined to the the liver and not associated with protal vein thrombosis;
  • To treat liver metastasis in:
    • Symptomatic patients with metastatic neuroendocrine tumors whose symptoms persist despite systemic therapy and who are not candidates for surgical resection;
    • Patients with liver-dominant metastatic uveal melanoma.

Not Medically Necessary

BCBSMT considers the use of TACE not medically necessary when the criteria for coverage outlined above is not met.

Advanced Member Notice of Financial Liability for Denied Services

When the criteria for coverage is not met, BCBSMT encourages all participating providers to have a member complete and sign an Advanced Member Notification (AMN) form stating that BCBSMT will not cover this service, supply, device, or drug. If an AMN is signed prior to delivery of the service, participating providers can balance bill the patient. If an AMN is not signed, participating providers are financially liable and cannot balance bill the BCBSMT member for denied services. Services provided by an out-of-state provider that are denied as not medically necessary are the financial responsibility of the patient even if an AMN is signed.

Refer to the Advanced Member Notification medical policy for more information. The AMN form is available at www.bcbsmt.com  (Click on Providers and then Forms).

Policy Guidelines

When using transcatheter hepatic arterial chemoembolization as a bridge to transplantation to prevent further tumor growth, the following patient characteristics apply: a single tumor less than 5 cm 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.

Rationale

This policy is based on a 2000 TEC Assessment (1) that 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 2000 TEC 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). (2-4) The influence of these and other clinical characteristics on prognosis have given rise to at least 4 staging systems. (4) Outcome within any prognostic category, however, can still be highly variable, which raised 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. [5-11]) For these reasons, the discussion of recent literature was limited to reports from randomized, controlled trials.

At the time of this update, 4 randomized, controlled trials comparing TACE to alternative treatments had been published since the 2000 TEC Assessment. (12-15). Survival was the primary endpoint in 3 of 4 studies (13-15); the primary endpoint in the fourth, a randomized phase II trial (12), was overall response rate. None of these studies reported quality of life data or effects of TACE on palliation of symptoms.

Salman et al. (12) 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. (13) reported a randomized comparison of TACE plus percutaneous ethanol injection (PEI) to PEI alone in 52 patients with “one to three HCC tumors measuring smaller than 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 (14, 15) 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 (15) tended to have more advanced disease based on Okuda stage, Eastern Cooperative Oncology Group (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. The UNOS policy and the above three indications are discussed further here.

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. (16) 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, international normalized ratio, 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 or smaller

T2: one nodule between 2.0 and 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 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. (17) 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. In addition, the UNOS policy appears to implicitly recognize the role of locoregional 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 greater than 200 ng/mL, an arteriogram confirming a tumor, a biopsy confirming HCC, chemoembolization of lesion, radiofrequency, cryo, or chemical ablation of lesion.” (16)

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. (18) 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. (19) 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. (20) 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 greater than 3 cm affected the dropout rate due to tumor progression. (21)

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 locoregional therapies including TACE specifically to downstage tumors to meet the University of California at San Francisco (UCSF) criteria. (22) Eligibility for locoregional 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 locoregional 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. (23-26) Certainly some patients with T3 lesions apparently are cured with liver transplant, although most experience recurrent tumor. For example, in the seminal 1996 study (16), 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. (23) 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. (27)

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. (28) 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 locoregional 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 locoregional 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 locoregional therapy. For those with T2 lesions, the recurrence rates were similar whether or not the patient received locoregional therapy. However, for T3 lesions (including both T3A and T3B), the 5-year recurrence-free survival was 85.9% for those who received locoregional 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 locoregional therapy compared to 80.6% in those who did not. The authors concluded that preoperative locoregional 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 locoregional 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. (29)

Summary

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 locoregional therapies. Protocols vary among institutions, and often how the type of locoregional 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 and colleagues reported on 56 cirrhotic patients with unresectable HCC undergoing at least one 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. (30) The two 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=0.0004). 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 et al. reported on the effectiveness of TACE for HCC in a North American population. (31) 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- to 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 and colleagues reported results from an 8-year prospective cohort study of TACE from Japan. (32) In this study, 8,510 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=0.0001), alpha-fetoprotein value (p=0.0001), maximum tumor size (p=0.0001), number of lesions (p=0.0001), and portal vein invasion (p=0.0001). 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 (14, 15) 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. Thus, the policy statement on treatment of unresectable hepatocellular cancer is revised to indicate it may be considered medically necessary.

TACE for Hepatic Metastases from Neuroendocrine Tumors

Ruutiainen and colleagues reported on a study of 67 patients comparing bland embolization to TACE in neuroendocrine tumors metatstatic to the liver. (33) In this study, 67 patients underwent 219 embolization procedures: 23 patients received primarily bland embolization with polyvinyl alcohol (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%, respectively, after chemoembolization and 0%, 0%, and 0%, respectively, after bland embolization, respectively (log-rank test, p=0.16). 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=0.18). 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 et al, who noted that in a retrospective series of 81 patients, hepatic artery embolization or chemoembolization resulted in symptomatic and radiographic response in most patients with carcinoid metastases to the liver. (34) Osborne and colleagues reported on a nonrandomized study of 59 patients with neuroendocrine tumors who received either cytoreduction or embolization for symptomatic hepatic metastases. (35) The duration of symptom relief (35 vs. 22 months) and survival (43 vs. 24 months) both favored the cytoreduction approach. The authors commented 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. (36) 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 and colleagues in 1995 that showed that TACE had a 36% response rate (cisplatin chemoembolization) compared to a 1% response rate to systemic chemotherapy. (37) Patel and colleagues 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 it was 21.9 months, for patients with stable disease, it was 8.7 months, and for patients with progressive disease, it was 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 used 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 nonprogression of lesions after TACE who had liver transplantation; median survival in this group was 92.3 months. (39) Thus, given these data, the data presented above (18–21), and the accepted role within the transplant community of using TACE to maintain size criteria, this indication is considered medically necessary. The candidate for TACE to maintain tumor size pretransplantation should have a single tumor smaller than 5 cm or no more than 3 tumors each smaller 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).

The National Comprehensive Cancer Network (NCCN) guidelines current at the time of the 2007-2008 update for hepatocellular carcinoma (v.2.2008) listed a number of ablation options, including chemoembolization, for patients with unresectable hepatocellular carcinoma; the guidelines for colon cancer (v.2.2008) do not list chemoembolization as a treatment for metastatic colon cancer; the guidelines for neuroendocrine tumors, carcinoid and islet cell tumors (v.1.2007) list hepatic regional therapy, including chemoembolization, as one of the options for those with symptomatic, progressive, or large, unresectable liver metastases. (40)

2009 Update

The policy was updated with a literature review using a MEDLINE® search conducted in June 2009.

TACE for Hepatic Metastases from Uveal Melanoma

Huppert et al. reported the results of a pilot trial of 14 patients with hepatic metastases from uveal melanoma who underwent TACE. (41) Patients received a mean of 2.4 treatments (34 total treatments among the 14 patients). Responses were partial for 8 patients (57%). Four patients (29%) had stable disease and 2 (14%) had tumor progression. Median time to progression was 8.5 months (range: 5–35 months), and median survival after the first TACE treatment was 14.5 months in responders and 10 months in nonresponders (p=NS). In this study, the survival rate was 86% at 6 months, 50% at 12 months, 28% at 18 months, and 14% at 24 months after the first TACE treatment. Survival advantage was most pronounced for patients with tumor occupying less than 25% of the liver volume (n=7) with a median of 17 months, versus 11 months in the 7 patients with more than 25% involvement of the liver (p=0.02). The authors state that, for comparison, with no treatment, survival after detection of liver metastases is 2–7 months with a median 1-year survival rate less than 30%. Response rates for systemic chemotherapy are less than 10%, and 20–50% with immunochemotherapy, but with only a median survival of 5–9 months and serious toxicity.

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. (42) 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 include TACE. (42)

The literature has reported a median survival in patients with liver-dominant colorectal metastases treated with chemoembolization from 7–23 months. (43, 44) 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 et al. 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. (45) 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). (46) 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 et al. compared salvage therapy for liver-dominant colorectal metastatic adenocarcinoma using TACE or 90-yttrium radioembolization. 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.

Guidelines

The current NCCN guidelines for hepatocellular carcinoma and ablation options (v.2.2009) remain unchanged. (47) The guidelines for colon cancer (v2.2009) are unchanged in that chemoembolization is not listed as a treatment for metastatic colon cancer. The guidelines for neuroendocrine tumors (v.1.2009) remain unchanged.

Rationale for Benefit Administration

This medical policy was developed through consideration of peer reviewed medical literature, FDA approval status, accepted standards of medical practice in Montana, Technology Evaluation Center evaluations, and the concept of medical necessity. BCBSMT reserves the right to make exceptions to policy that benefit the member when advances in technology or new medical information become available.

The purpose of medical policy is to guide coverage decisions and is not intended to influence treatment decisions. Providers are expected to make treatment decisions based on their medical judgment. Blue Cross and Blue Shield of Montana recognizes the rapidly changing nature of technological development and welcomes provider feedback on all medical policies.

When using this policy to determine whether a service, supply or device will be covered please note that member contract language will take precedence over medical policy when there is a conflict.

Procedural Codes: 37204, 75894
References
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  4. Yu AS, Keeffe EB. Management of hepatocellular carcinoma. Rev Gastroenterol Disord 2003; 3(1):8-24.
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Transcatheter Arterial Embolization for Cancer Treatment