BlueCross and BlueShield of Montana Medical Policy/Codes
Transcatheter Arterial Chemoembolization (TACE) to Treat Primary or Metastatic Liver Malignancies
Chapter: Therapies
Current Effective Date: September 24, 2013
Original Effective Date: May 01, 2006
Publish Date: September 24, 2013
Revised Dates: January 2, 2008; November 7, 2008; March 1, 2010; March 16, 2011; December 7, 2012; July 30, 2013
Description

Transcatheter arterial chemoembolization (TACE) of the liver is a proposed alternative to conventional or intra-arterial chemotherapy, and to various nonsurgical ablative techniques, to treat resectable and nonresectable tumors.  TACE combines the infusion of chemotherapeutic drugs with particle embolization. Tumor ischemia secondary to the embolization raises the drug concentration compared to infusion alone, extending the retention of the chemotherapeutic agent and decreasing systemic toxicity.  The liver is especially amenable to such an approach, given its distinct lobular anatomy, the existence of two independent blood supplies, and the ability of healthy hepatic tissue to grow and thus compensate for tissue mass lost during chemoembolization. 

TACE of the liver has been associated with potentially life-threatening toxicities and complications, including severe postembolism 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 and chemotherapy administration {administered systemically or by hepatic artery infusion (HAI). HAI involves continuous infusion of chemotherapy with an implanted pump, while TACE is administered episodically.  Also, hepatic artery infusion does not involve the use of embolic material.

The TACE procedure requires hospitalization for placement of the hepatic artery catheter and work-up 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 super selective 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 one lobe of the liver is treated during a single session, with subsequent chemoembolization procedure scheduled from five to six weeks later.  In addition, since the embolized vessel recanalizes, chemoembolization can be repeated as many times as necessary.

Policy

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions.  Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply.  If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Medically Necessary

Blue Cross and Blue Shield of Montana (BCBSMT) may consider transcatheter hepatic arterial chemoembolization (TACE) medically necessary to treat hepatocellular cancer that is unresectable but confined to the liver and not associated with portal vein thrombosis.

TACE may be considered medically necessary 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.

TACE may be considered medically necessary to treat liver metastasis in patients with liver-dominant metastatic uveal melanoma.

TACE may be considered medically necessary 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 meeting ALL the following criteria:

  • a single tumor less than 5 cm or no more than three tumors each less than 3 cm in size,
  • absence of extrahepatic disease or vascular invasion, and
  • Child-Pugh score of either A or B.

Investigational

BCBSMT considers TACE experimental, investigational and unproven to treat liver metastases from any other tumors or to treat hepatocellular cancer that does not meet the criteria noted above, including recurrent hepatocellular carcinoma.

TACE is considered experimental, investigational and unproven as neoadjuvant or adjuvant therapy in hepatocellular cancer that is considered resectable.

TACE is considered experimental, investigational and unproven to treat hepatocellular tumors prior to liver transplantation except as noted above.

Rationale

This policy is based on a 2000 Blue Cross Blue Shield Association Technology Assessment that evaluated patients with the following indications:

  • resectable primary hepatocellular carcinoma (HCC), in which outcomes were compared to those with surgery alone;
  • HCC that has recurred after resection, in which outcomes were compared with systemic chemotherapy, hepatic artery infusion, and cytoreductive surgery;
  • 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;
  • unresectable hepatic metastases from resected colorectal cancer, in which outcomes were compared with systemic chemotherapy and hepatic artery infusion; and
  • 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 BCBSA 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 between groups in any of the trials.
  • There were no controlled trials focusing on patients with unresectable hepatocellular 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 three 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.  There were also inadequate data to permit conclusions regarding tumor response rates and survival. In spite of this, neuroendocrine hormone producing tumors can produce debilitating symptoms such as flushing, wheezing, and diarrhea.  As stated above, case series reported TACE reduced these symptoms and thus these patients may merit individual consideration.

2008 Update

A search of the MedLine database was performed for the period of May 2006 through July 2008. Search results consisted mostly of 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 four 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 BCBSA TEC Assessment. Survival was the primary endpoint in three of four 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 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 two 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 two 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 BCBSA 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 United Network of Organ Sharing (UNOS) liver allocation policy, which prioritizes patients for receiving donor livers.

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.”

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. Eligibility for locoregional therapy seeking to downstage patients included either one nodule between 5cm and 8cm in diameter; two or three nodules with at least one between 3 and 5 cm in diameter, with sum of diameters no greater than 8 cm; or four or five 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. 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 smaller or no more than three 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.

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 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.

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. 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  seven 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. 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 six 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 two 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. 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 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 coverage 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 metastatic 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, 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.  Osborne and colleagues 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 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.

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 and colleagues in 1995 that showed that TACE had a 36% response rate (cisplatin chemoembolization) compared to a 1% response rate to systemic chemotherapy.  Patel and colleagues reported on BCNU (Carmustine) treatment for uveal melanoma and demonstrated that those who responded had improved survival.  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

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 UNOS revised its liver allocation policy, such that wait times for patients with HCC meeting the “Milan criteria” have now declined.   Milan criteria is defined as no evidence of extrahepatic tumor and unifocal tumor mass < 5 cm in diameter or multifocal tumors < 4 in number, each < 3 cm in diameter.

Given these limitations the following case series have been reported. Graziadei and colleagues reported on patients with HCC awaiting transplantation; all underwent TACE every six to eight 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 one and three years was 6.25 and 23%, respectively. Tumors greater than 3 cm affected the dropout rate due to tumor progression.  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 nonprogression 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 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 current NCCN guidelines for hepatocellular carcinoma (v.2.2008) list 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.

2010 Update

A search of peer reviewed literature was conducted through October 2010. 

Uveal Melanoma Metastatic to Liver

Huppert et al. reported the results of a pilot trial of 14 patients with hepatic metastases from uveal melanoma that underwent TACE.  Patients received a mean of 2.4 treatments (34 total treatments among the 14 patients).  Responses were partial for eight patients (57%).  Four patients (29%) had stable disease and two (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 ten months in nonresponders (p=NS).  In this study, the survival rate was 86% at six months, 50% at twelve months, 28% at eighteen months, and 14% at twenty four 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 seven 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 one-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 as a Bridge to Transplant

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.

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 include TACE.

The literature has reported a median survival in patients with liver-dominant colorectal metastases treated with chemoembolization from 7–23 months.  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.  Of the 463 patients, 67% had five or more metastases, 8% had one metastasis, 10% had two, and 14% had three or four.  Patients were treated at four-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 whom untreated patients had a survival rate of  7–8 months).  One-year survival rate after TACE was 62% and 28% at two 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.

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.  They evaluated 18 studies, including three 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).  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 two 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.  They showed that the 5-year disease-free survival rates of the patients who received more than two 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 three 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.

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.

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.   An addition Phase III trial is recruiting patients with HCC with one lesion 5 cm or larger or multinodular disease with four 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.

Coding

Disclaimer for coding information on Medical Policies           

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy.  They may not be all-inclusive.           

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers.  Only the written coverage position in a medical policy should be used for such determinations.           

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

ICD-9 Codes
99.25, 155.0 - 155.2, 197.7
ICD-10 Codes
C22.0-C22.9, C78.7, 3E05005, 3E05305, 3E06005, 3E06305
Procedural Codes: 37204, 75894, Q0084
References
  1. Madden, M.V., Krige, L.E., et al.  Randomized trial of targeted chemotherapy with Lipodol ® and 5-epidoxorubicin compared with symptomatic treatment for hepatoma. GUT (1993) 34(11):1598-600.
  2. Lang EK, Brown CL. Colorectal metastases to the liver: selective chemoembolization. Radiology 1993; 189(2):417-22.
  3. Groupe d’Etude et de Traitement du Carcinome Hepatocellulaire.  A comparison of Lipiodol® chemoembolization and conservative treatment for unresectable hepatocellular carcinoma.  New England Journal of Medicine (1995) 332(19):1256-61.
  4. Stuart K, Huberman M, Posner M et al. Chemoembolization for colorectal metastases. Proc Am Soc Clin Oncol 1995; 14:190. Abstract.
  5. Bedikian AY, Legha SS, Mavligit G et al. Treatment of uveal melanoma metastatic to the liver: a review of the M.D. Anderson Cancer Center experience and prognostic factors. Cancer 1995; 76(9):1665-70.
  6. Mazzaferro V, Regalia E, Doci R et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996; 334(11):693-9.
  7. Pelletier, G., Ducreau, M., et al.  Treatment of unresectable hepatocellular carcinoma with Lipiodol chemoembolization: a multicenter randomized trial. Journal of Hepatology (1998) 29(1):129-34.
  8. Zhang Z, Liu Q, He J et al. The effect of preoperative transcatheter hepatic arterial chemoembolization on disease-free survival after hepatectomy for hepatocellular carcinoma. Cancer 2000; 89(12):2606-12.
  9. Transcatheter Arterial Chemoembolization of Hepatic Tumors. Chicago, Illinois, Blue Cross Blue Shield Association - Technology Evaluation Center Assessment Program (2001 March) 15(22):1-50.
  10. Yao FY, Ferrell L, Bass NM et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology 2001; 33(6):1394-403.
  11. Koda, M., Murawaki, Y., et al.  Combination therapy with transcatheter arterial chemoembolization and percutaneous ethanol injection compared with percutaneous ethanol injection alone for patients with small hepatocellular carcinoma.  Cancer (2001) 92(6):1516-24.
  12. Bruis, J., Llovet, J.M.  Prognostic assessment and evaluation of the benefits of treatment.  Journal of Clinical Gastroenterology (2002) 35(5 supplement 2): S138-42.
  13. Bruis, J., Llovet, J.M.  Prognostic prediction and treatment strategy in hepatocellular carcinoma.  Hepatology (2002) 35(3):519-24.
  14. Adam, A.   Interventional radiology in the treatment of hepatic metastases.  Cancer Treatment Reviews (2002) 28(2):93-9.
  15. Cha, C., DeMatteo, R.P., et al.  Surgery and ablative therapy for hepatocellular carcinoma. Journal of clinical Gastroenterology (2002) 35(5 supplement 2): S130-7.
  16. Geschwind, J.F.  Chemoembolization for hepatocellular carcinoma: where does the truth lie?  Journal of Vascular and Interventional Radiology (2002) 13(10):991-4.
  17. Llovet, J.M.  Evidence-based medicine in the treatment of hepatocellular carcinoma.  Journal of Gastroenterology and Hepatology  (2002) 17(supplement 3):S429-33.
  18. Camma, C., Schepis,F., et al.  Transarterial chemoembolization for unresectable hepatocellular carcinoma: meta-analysis of randomized controlled trials. Radiology (2002) 224(1):47-54.
  19. Schwartz, J.D.. Schwartz, M., et al.  Neoadjuvent and adjuvant therapy for resectable hepatocellular carcinoma: review of the randomized clinical trials. Lancet Oncology (2002)3(10):593-603.
  20. Salman, H.S., Cynamon, J., et al.  Randomized phase II trial of embolization therapy versus chemoembolization therapy in previously treated patients with carcinoma metastatic to the liver. Clinical Colorectal Cancer (2002) 2(3):173-9.
  21. Lo, C.M., Ngan, H., et al.  Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma.  Hepatology (2002) 35(5):1164-71.
  22. Llovet, J.M., Real, M.I., et al.  Arterial embolization or chemoembolization versus symptomatic treatment on patients with unresectable hepatocellular carcinoma: a randomized controlled trial.  Lancet (2002) 359(9319):1734-9.
  23. Yao FY, Ferrell L, Bass NM et al. Liver transplantation for hepatocellular carcinoma: comparison of the proposed UCSF criteria with the Milan criteria and the Pittsburgh modified TNM criteria. Liver Transpl 2002; 8(9):765-74.
  24. Sun, H.C., Tang, Z.Y., et al.  Preventive treatments for recurrence after curative resection of hepatocellular carcinoma - a literature review of randomized controlled trials.  World Journal of Gastroenterology (2003) 9(4):635-40.
  25. Trinchet, J.C., Ganne-Carrie, N., Beaugrand, M., Review article: intra-arterial treatments in patients with hepatocellular carcinoma.  Alimentary Pharmacology and Therapeutics (2003) 17(suppl2):111-8.
  26. Yu, A.S., Keeffe, E.B. Management of hepatocellular carcinoma. Reviews in Gastroenterological Disorders (2003) 3(1):8-24.
  27. Llovet,J., Bruix, J. for the Barcelona-Clinic Liver Cancer Group.  Systematic review of randomized controlled trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology (2003) 37(2):429-42.
  28. Myers,R.P.,  Meta-analysis of transarterial embolization in patients with unresectable hepatocellular carcinoma.  Radiology (2003) 227(2):611-2.
  29. Graziadei, I.W., Sandmueller, H., et al.  Chemoembolization followed by liver transplantation for hepatocellular carcinoma impedes tumor progression while on the waiting list and leads to excellent outcome.  Liver Transplantation (2003) 9(6):557-63.
  30. Fernandez JA, Robles R, Marin C et al. Can we expand the indications for liver transplantation among hepatocellular carcinoma patients with increased tumor size? Transplant Proc 2003; 35(5):1818-20.
  31. Gupta S, Yao JC, Ahrar K et al. Hepatic artery embolization and chemoembolization for treatment of patients with metastatic carcinoid tumors: the M.D. Anderson experience. Cancer J 2003; 9(4):241-3.
  32. Vogl TJ, Mack MG, Balzer JO et al. Liver metastases: neoadjuvant downsizing with transarterial chemoembolization before laser-induced thermotherapy. Radiology 2003; 229(2):457-64.
  33. Maddala, Y.K., Stadheim, L., et al.  Drop-out rates of patients with hepatocellular cancer listed for liver transplantation: outcome with chemoembolization.  Liver Transplantation (2004) 10(3):449-55.
  34. Fisher RA, Maluf D, Cotterell AH et al. Non-resective ablation therapy for hepatocellular carcinoma: effectiveness measured by intention-to-treat and dropout from liver transplant waiting list. Clin Transplant 2004; 18(5):502-12.
  35. Yamashiki N, Tateishi R, Yoshida H et al. Ablation therapy in containing extension of hepatocellular carcinoma: a simulative analysis of dropout from the waiting list for liver transplantation. Liver Transpl 2005; 11(5):508-14.
  36. Yao FY, Hirose R, LaBerge JM et al. A prospective study on downstaging of hepatocellular carcinoma prior to liver transplantation. Liver Transpl 2005; 11(12):1505-14.
  37. Sauer P, Kraus TW, Schemmer P et al. Liver transplantation for hepatocellular carcinoma: Is there evidence for expanding the selection criteria? Transplantation 2005; 80(1 suppl):S105-8.
  38. Merli M, Nicolini G, Gentili F et al. Predictive factors of outcome after liver transplantation in patients with cirrhosis and hepatocellular carcinoma. Transplant Proc 2005; 37(6):2535-40.
  39. Yao FY, Kinkhabwala M, LaBerge JM et al. The impact of pre-operative loco-regional therapy on outcome after liver transplantation for hepatocellular carcinoma. Am J Transplant 2005; 5(4 pt 1):795-804.
  40. Palmer DH, Johnson PJ. Pre-operative locoregional therapy and liver transplantation for hepatocellular carcinoma: time for a randomized controlled trial. Am J Transplant 2005; 5(4 pt 1):641-2.
  41. Patel K, Sullivan K, Berd D et al. Chemoembolization of the hepatic artery with BCNU for metastatic uveal melanoma: results of a phase II study. Melanoma Res 2005; 15(4):297-304.
  42. Biselli M, Andreone P, Gramenzi A et al. Transcatheter arterial chemoembolization therapy for patients with hepatocellular carcinoma: a case-controlled study. Clin Gastroenterol Hepatol 2005; 3(9):918-25.
  43. Molinari M, Kachura JR, Dixon E et al. Transarterial chemoembolization for advanced hepatocellular carcinoma: results from a North American cancer centre. Clin Oncol (R Coll Radiol) 2006; 18(9):684-92.
  44. Osborne DA, Zervos EE, Strosberg J et al. Improved outcome with cytoreduction versus embolization for symptomatic hepatic metastases of carcinoid and neuroendocrine tumors. Ann Surg Oncol 2006; 13(4):572-81.
  45. Li Q, Wang J, Sun Y et al. Efficacy of postoperative transarterial chemoembolization and portal vein chemotherapy for patients with hepatocellular carcinoma complicated by portal vein tumor thrombosis—a randomized study. World J Surg 2006; 30(11):2004-11.
  46. Takayasu K, Arii S, Ikai I et al. Prospective cohort study of transarterial chemoembolization for unresectable hepatocelluar carcinoma in 8510 patients. Gastroenterology 2006; 131(2):461-9.
  47. Ruutiainen AT, Soulen MC, Tuite CM et al. Chemoembolization and bland embolization of neuroendocrine tumor metastases to the liver. J Vasc Interv Radiol 2007; 18(7):847-55.
  48. Choi GH, Kim DH, Kang CM et al. Is preoperative transarterial chemoembolization needed for a resectable hepatocellular carcinoma? World J Surg 2007; 31(12):2370-7.
  49. Obed A, Beham A, Pullmann K et al. Patients without hepatocellular carcinoma progression after transarterial chemoembolization benefit from liver transplantation. World J Gastroenterol 2007; 13(5):761-7.
  50. Sharma KV, Gould JE, Harbour JW et al. Hepatic arterial chemoembolization for management of metastatic melanoma. AJR Am J Roentgenol 2008; 190(1):99-104,
  51. Transcatheter Arterial Chemoembolization to Treat Primary or Metastatic Liver Malignancies. 
  52. Vogl TJ, Gruber T, Balzer JO et al. Repeated transarterial chemoembolization in the treatment of liver metastases of colorectal cancer: prospective study. Radiology 2009; 250(1):281-9.
  53. Huppert PE, Fierlbeck G, Pereira P et al. Transarterial chemoembolization of liver metastases in patients with uveal melanoma. Eur J Radiol 2009 May 19 [Epub ahead of print].
  54. Hong K, McBride JD, Georgiades CS et al. Salvage therapy for liver-dominant colorectal metastatic adenocarcinoma: comparison between transcatheter arterial chemoembolization versus yttrium-90 radioembolization. J Vasc Interv Radiol 2009; 20(3):360-7.
  55. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Available online at: http://www.nccn.org/professionals/physician_gls/default.asp Last accessed June 2009
  56. Mabed M, Esmaeel M, El-Khodary T et al. A randomized controlled trial of transcatheter arterial chemoembolization with lipiodol, doxorubicin and cisplatin versus intravenous doxorubicin for patients with unresectable hepatocellular carcinoma. Eur J Cancer Care 2009; 18(5):492-9.
  57. Chua TC, Liauw W, Saxena A et al. Systematic review of neoadjuvant transarterial chemoembolization for resectable hepatocellular carcinoma. Liver Transpl 2009; 30(2):166-74.
  58. Zhou WP, Lai EC, Li AJ et al. A prospective, randomized, controlled trial of preoperative transarterial chemoembolization for resectable large hepatocellular carcinoma. Ann Surg 2009; 249(2):195-202.
  59. Lewandowski RJ, Kulik LM, Riaz A et al. A comparative analysis of transarterial downstaging for hepatocellular carcinoma: chemoembolization versus radioembolization. Am J Transplant 2009; 9(8):1920-8.
  60. Pomfret EA, Washburn K, Wald C et al. Report of a national conference on liver allocation in patients with hepatocellular carcinoma in the United States. Liver Transpl 2010; 16(3):262-78.
  61. Nazario J, Gupta S. Transarterial liver-directed therapies of neuroendocrine hepatic metastases. Semin Oncol 2010; 37(2):118-26.
  62. Sato T. Locoregional management of hepatic metastasis from primary uveal melanoma. Semin Oncol 2010; 37(2):127-38.
  63. Vogl TJ, Naguib NN, Nour-Eldin NE et al. Transarterial chemoembolization (TACE) with mitomycin C and gemcitabine for liver metastases in breast cancer. Eur Radiol 2010; 20(1):173-80.
  64. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Available at: http://www.nccn.org  (Last accessed September, 2010)
  65. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2010 October) Therapy 8.01.11.
History
October 2010 Removed CPT 36245 from the policy.
March 2011  Revised title, rationale, references. Policy statement added that transcatheter hepatic arterial chemoembolization is considered investigational "as neoadjuvant or adjuvant therapy in hepatocellular cancer that is considered resectable and
to treat hepatocellular tumors prior to liver transplantation except as noted above." Denial reason changed from "not medically necessary" to "investigational."
December 2012 Policy updated with literature search. References 3, 8, 12 and 24-28 added; references renumbered. Policy statement added that TACE for unresectable cholangiocarcinoma is considered investigational. Clinical vetting obtained.
July 2013 Policy formatting and language revised.  Policy statement unchanged.  Removed HCPCs code Q0083 and added Q0084.
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Transcatheter Arterial Chemoembolization (TACE) to Treat Primary or Metastatic Liver Malignancies