Medical Policy

 

Subject: Transcatheter Arterial Chemoembolization (TACE) and Transcatheter Arterial Embolization (TAE) for Malignant Lesions Outside the Liver except Central Nervous System (CNS) and Spinal Cord
Document #: RAD.00059 Publish Date:    06/28/2017
Status: Revised Last Review Date:    05/04/2017

Description/Scope

This document addresses the use of transcatheter arterial chemoembolization (TACE) and transcatheter arterial embolization (TAE) for malignant lesions outside the liver, used as adjunct therapeutic interventions prior to operative resection or for palliation of symptoms.

Note:

Note: For additional information please refer to the following related documents:

Position Statement

Investigational and Not Medically Necessary:

Transcatheter arterial chemoembolization and transcatheter arterial embolization are considered investigational and not medically necessary for malignant lesions outside the liver.

Rationale

TACE and TAE are catheter-based embolization procedures performed with or without chemotherapeutic agents. TACE involves the regional injection of a form of chemotherapeutic or antitumor agent immediately followed by injection of an embolizing agent into the arterial vasculature supplying a tumor. TAE involves injecting an embolizing agent without a chemotherapeutic agent into the arterial vasculature. Both procedures have a tumoricidal effect on the targeted tumor(s) and have been proposed for tumor destruction, preoperative tumor bulk reduction and palliative treatment. While there are data in the peer-reviewed literature to support TACE and TAE for hepatic (liver) indications, there is limited evidence supporting their use for non-hepatic malignant indications.

TAE for Carotid Body Tumors

Bercin and colleagues (2015) conducted a small retrospective case review to determine the efficiency of preoperative embolization on vascular rupture rates during surgery in individuals with malignant carotid body tumors. A total of 13 records were included in the analysis that compared preoperative carotid body tumor embolization (n=7 cases) to no tumor embolization (n=6 cases). Data was collected on demographics, preoperative anatomical presentation of the carotid artery (including blood flow), tumor size, and complications of embolization (blood loss, other injury). The mean age of individuals was 48 years (range 22-70 years). A total of 12 of 13 individuals had stage II tumors with a mean diameter of 4.42 centimeters. Relative rates of blood flow reduction during embolization were greater than 50% in 4 individuals and 25%-50% in 3 individuals. Carotid artery injury was recorded in 4 embolized individuals (57%) and 1 non-embolized individual. There were no significant differences between carotid artery rupture and embolization, blood loss, tumor size, and supplying artery. The authors concluded that the benefit of embolization before surgical excision of carotid body tumor is "controversial" and "does not appear to be an advantage in reducing intraoperative blood loss, ease of dissection, and reducing the duration of the operative procedure following embolization."

TACE and TAE for Kidney Cancer

Renal artery embolization (RAE) has been used as an adjunct procedure prior to resection of locally advanced renal tumors, but its role remains controversial given the lack of randomized prospective trials demonstrating a clinical benefit. Initially it was hypothesized that preoperative TAE may lead to improved survival in individuals with renal cell carcinoma (RCC) through immunomodulation, where TAE induced tumor necrosis promoted tumor-specific natural killer cells (Bakke, 1982). Several older studies suggest potential clinical use.

Nurmi and colleagues (1987) studied RAE for the palliative treatment of 25 individuals with renal adenocarcinoma. The tumors ranged in size from 4 to 21 centimeters (cm) (mean size, 11 cm). At the time of embolization, 15 participants had distant metastases to sites in the lung (n=6), bony skeleton (n=3), liver (n=3), lungs/bones (n=2), and liver/bone (n=1). A total of 10 participants had no metastases. Symptoms experienced by the participants included severe pain (n=6) and gross hematuria (n=14); 5 participants were treated for disease progression. Renal blood flow was demonstrated in all participants along with any evidence of kidney function. Post-procedure symptoms were experienced in 24 participants for 1 to 5 days. There was 1 death in an individual who had an extensive history of cancer. Severe local pain due to the tumor was relieved in 3 of 6 participants despite disease progression. Gross hematuria persisted in 3 of 14 individuals. This small study found that embolization could palliate pain but had no impact on disease progression or survival.

Zielinski and colleagues (2000) retrospectively compared the survival benefit of preoperative RAE followed by radical nephrectomy (n=118) to radical nephrectomy alone (n=116) in a matched group analysis of individuals selected from a series of 474 persons with RCC. Individuals were selected for embolization based on preference of a urologist responsible for their care. As a result of this selection process, criteria for preoperative embolization was difficult to define; however, embolized individuals were expected to have T2-T3 tumors, tumors > 6 cms as demonstrated on preoperative imaging studies, M0 disease, and good performance status. The timing of embolization prior to surgery ranged from 1 to 3 days (66 individuals, 56%), 4 days (22 individuals, 19%), and 5 to 13 days (30 individuals, 25%).  Embolization was performed with various agents, most frequently a gelatin sponge product or wire coil device. The overall 5- and 10-year survival for the 118 individuals embolized before nephrectomy was 62% and 47%, respectively, and 35% and 23%, respectively for the matched group of 116 individuals treated with surgery alone (p=0.01). The reported favorable survival benefit associated with preoperative TAE for RCC needs to be interpreted with caution, as the data was derived from a nonrandomized, single-institution clinical trial.

Maxwell and colleagues (2007) studied a case series of 19 consecutive subjects undergoing palliative treatment of RCC with cytoreductive RAE. Unresectable disease was present in 11 subjects and potentially resectable disease was present in 8 subjects; the latter were felt to be unfit for surgery. Presenting symptoms included hematuria, pain, and nephrotic syndrome. Post embolization syndrome occurred within 1 to 3 days. A total of 8 subjects experienced mild flank pain, 5 subjects developed fever, and 2 subjects experienced nausea. At the conclusion of the study, 12 individuals had died and 7 were still alive with an overall median survival of 6 months. The study concluded that RAE is not a curative treatment and minimally altered the general course of the disease, but it did provide some palliation of local symptoms for advanced renal malignancy; therefore, comparison of cytoreductive embolization should be included in future studies of individuals with metastatic RCC.

Despite interest that TAE in the preoperative management of RCC may facilitate dissection secondary to the resultant tissue plane edema, reduce blood loss, and decrease the extent of tumor thrombus, these benefits have been suggested primarily in small, case series and uncontrolled studies and have not been established in larger, randomized, prospective trials. May and colleagues (2009) conducted a large matched-pair retrospective study of individuals with RCC treated at a single center having either RAE prior to nephrectomy or nephrectomy alone. The pairing was based upon age, gender, clinical tumor size, grading, staging histology and microvascular invasion. Individuals with RAE (Group 1; n=189) were matched to individuals having surgery alone (Group 2; n=189). Cancer specific survival (CSS) and overall survival (OS) were defined as the primary endpoints. The CSS at 1, 5, and 8 years for Group 1 was 95%, 79%, and 70%; and, for Group 2, 93%, 83%, and 79% (p=0.085), respectively. The OS at 1, 5, and 8 years for Group 1 was 93%, 73%, and 62%; and, for Group 2, 91%, 75%, and 67%, respectively (p=0.677). Based on this data, the authors concluded that RAE prior to nephrectomy did not improve clinical outcomes or demonstrate a survival benefit for individuals with RCC.

Liu and colleagues (2008) conducted a randomized, prospective trial in China investigating TACE followed by tumor resection in children diagnosed with Wilms' tumor. A cohort of 44 children, ages 6 months to 12 years were allocated into 2 groups: Group 1 (n=24) participants were treated with TACE preoperatively; Group 2 participants, the control group (n=20), were treated with tumor resection only and without TACE. The 2-year tumor-free survival rate was 83.3% for children in the TACE group compared to 10% for those in the control group (p<0.001). The rate of tumor recurrence and death within 1 year was 16.6% (4 of 24) for children in the TACE group compared to 60% (12 of 20) for those in the control group (p<0.001). While the results of this small study suggest that children with Wilms' tumor may benefit from preoperative TACE, randomized comparative trials of larger sample size are needed to confirm these preliminary findings.

The current National Comprehensive Cancer Network® (NCCN) Clinical Practice Guidelines (CPGs) in Oncology® for kidney cancer do not include a recommendation for the use of TACE or TAE for the treatment of RCC (NCCN, 2016).

TACE and TAE for Bone Cancer

Yang and colleagues (2011) conducted a retrospective review of 60 individuals with sacral tumors to determine the value of preoperative TAE. The authors evaluated intraoperative blood loss, need for transfusion, treatment, local recurrence and surgical complications. There were no symptomatic complications associated with TAE. All tumors were resected without intraoperative shock or death. Those having surgery 1 day post-TAE tended to have lower blood loss than those having surgery 2 to 3 days post-TAE, but the difference was not statistically significant (p=0.073 and p=0.086, respectively). With regard to surgical technique, those having a wide excisional margin (n=8) had no local recurrence or evidence of disease. Those having a marginal excision had local recurrence (6 of 34 individuals) and those having an intralesional excision had local recurrence (13 of 18 individuals). The average follow-up was 75.2 months (range, 15 to 180 months). During the follow-up period, 22 individuals presented with varying degrees of neurological dysfunction in the form of motor weakness or loss of bowel/bladder control. Based on these findings, the authors concluded that preoperative TAE may significantly reduce intraoperative hemorrhage. Limitations in drawing conclusions from this study include the lack of an active comparator control and retrospective design.

Koike and colleagues (2010) conducted a single center retrospective study evaluating both TACE and TAE as palliative treatments for symptomatic bone metastases. A total of 24 hypervascular lesions in 18 subjects were treated with either TACE or TAE. Devascularization of targeted lesions was obtained in 75% (18 of 24) of the lesions without serious complication. Pain relief was obtained in 20 lesions (83%) with a significant decrease in the visual analog scale (VAS) for pain score (5.08 pre-procedure VAS vs. 1.3 post-procedure; p<0.001). Mean time to pain relief was 1.6 days. Primary lesions included hepatocellular, colorectal, renal, ovarian, thyroid and cervical cancers. Symptomatic lesions treated were thoracic/lumbar spine, pelvis, rib and femur. The treatment effect of TACE and TAE was difficult to evaluate since participants received a variety of adjuvant therapies including radiation therapy, bisphosphonates and steroids during their clinical course limiting comparison; in addition, the mean follow-up period was limited to 7.5 months (range, 1 to 29 months).

The NCCN CPG for bone cancer includes a recommendation for the use of selective serial embolizations in the treatment of metastatic giant cell tumor of the bone (GCTB) (NCCN, 2016). The 2A recommendation is based on two single case studies of giant cell tumors; one case study involving presurgical embolization of a proximal humerus tumor with cortical bone destruction extending to the shoulder joint (Emori, 2012) and a single case study involving embolization of a sacral tumor (Onishi, 2010). In addition, two small retrospective case series (Hosalkar, 2007 [n=9]; Lin, 2002 [n=18]) were cited with the 2A recommendation. Both case series evaluated mid- to long-term outcomes of serial arterial embolization as the primary treatment modality for large giant cell tumors of the sacrum. In the study by Lin and colleagues (2002), 14 of the 18 persons responded favorably to embolization with improvement in pain and neurologic symptoms. It was noted that 9 of the 18 persons also received intraarterial cisplatin as part of the treatment plan. There was 1 death that occurred 1 day after embolization. With long-term follow-up, 3 persons developed late disease recurrences within the sacrum. Randomized trials comparing embolization to other therapies (such as, radiation, denosumab, and interferon) have not been reported.

TACE and TAE for Metastatic Thyroid Cancer

The NCCN CPG for thyroid cancer includes a recommendation to consider embolization as an option in the treatment of metastatic follicular, Hürthle cell, and papillary thyroid carcinoma (NCCN, 2016). The therapeutic approach for metastatic disease depends on the site and number of tumor foci. The 2A recommendation is based on a single study of the effects of selective embolization in individuals with symptomatic bone metastases from differentiated thyroid carcinoma. A total of 41 embolizations were performed in 16 individuals who were followed-up (range, 2 months to 8.6 years) after the first embolization by evaluation of clinical symptoms and tumor dimensions. Success was defined as an improvement in clinical symptoms without tumor progression. Embolization was reported as successful in 24 of 41 occasions (59%). A total of 26 embolizations were preceded or followed-up by additional therapies, consisting of surgery (laminectomy), external irradiation, or radioiodine. The authors reported, however, that subgroup analysis revealed the additional therapies did not influence the success rate, but a potential effect on success duration may have been present. For embolizations without additional radioiodine or external irradiation therapy, the median success duration was 6.5 months; for embolizations combined with additional radioiodine or external irradiation, the median success was 15 months (p=0.0146). The eventual health outcomes of these individuals were unfavorable, as 9 persons died and 5 persons had progressive disease. Despite a rapid induction and relief of symptoms, the treatment effect was transient and lacked durability (Eustatia-Rutten, 2003). For follicular, Hürthle cell, and papillary thyroid carcinoma, randomized comparative trials with other therapies, such as surgical palliation, radioiodine treatment, and/or external beam radiation, intravenous bisphosphonate, denusomab, and small molecular kinase inhibitors or systemic therapy have not been reported.

Other than bone metastases, for medullary thyroid carcinoma, recurrent or persistent disease, the NCCN recommendations state: for symptomatic, distant metastases "consider palliative resection, ablation (for example, radiofrequency [RFA], embolization, or other regional therapy), or other regional treatment," or chemotherapy (category 1 and 2A recommendations), "EBRT for focal symptoms," or participation in a clinical trial; and, for asymptomatic, distant metastases "observe, or consider resection (if possible), ablation (for example, RFA, embolization, or other regional therapy), or vandetanib (category 1), or cabozantinib (category 1) if not resectable and structurally progressive disease." The 2A recommendation concludes, however, that "these interventions may be considered for asymptomatic distant metastases (especially for progressive disease), but observation is acceptable given the lack of data regarding alteration in outcome." Randomized trials comparing embolization with other therapies for locoregional disease in the absence of distant metastases and disseminated symptomatic metastases have not been reported.

Other Considerations

The current NCCN CPGs do not include a recommendation for TACE or TAE for the treatment of malignant lesions outside the liver for other cancers (except GCTB and metastatic thyroid cancer, as discussed above), including, colon, gastric, head and neck (such as, carotid body tumors), rectal, pancreatic, and prostate cancer.

Further study is needed to establish a clinical outcome benefit of TACE and TAE in the management of primary or metastatic tumors outside of the liver. Evidence published to date is limited to retrospective case series and single or small case reports. Prospective, randomized controlled trials are needed to better define the role of TACE and TAE in the management of these conditions.

Background/Overview

TACE and TAE have been proposed as alternatives to conventional systemic or intra-arterial chemotherapy as well as various nonsurgical ablative techniques for the treatment of resectable and nonresectable tumors. TACE and TAE target the arterial blood supply to tumors utilizing selective catheter-based infusion of particles, with or without chemotherapeutic agents. TAE involves the infusion of lipiodol (without a chemotherapeutic agent) and TACE involves the delivery of chemotherapeutic agents, either alone or in combination, mixed with a viscous embolic material, such as lipiodol. TAE may also involve the use of coils and balloons for embolization. Both TAE and TACE are followed by infusion of embolic agents, such as liquid embolitics (absolute alcohol), gelatin sponge particles, polyvinyl alcohol particles (PVA), or hydrophilic, polyacrylamide microporous beads (microspheres). The rationale for use of TACE is that infusion of viscous material containing one or more antineoplastic agents may exert synergistic effects on the tumor while minimizing systemic toxicities associated with oral or intravenous chemotherapy.

Definitions

Adenocarcinoma: A type of cancer that develops in cells lining glandular types of internal organs, such as the lungs, breasts, colon, prostate, stomach, pancreas, and cervix.

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

Tumoricidal: Any treatment that is destructive to cancer cells.

Coding

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

When services are Investigational and Not Medically Necessary:
When the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

CPT  
37243 Vascular 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
   
ICD-10 Diagnosis  
  For the following diagnoses when the procedure is related to treatment or palliation of symptoms of the malignant lesion outside the liver:
C00.0-C21.8 Malignant neoplasm of lip, oral cavity and pharynx, esophagus, stomach, small intestine, colon, rectosigmoid junction, rectum, anus and anal canal
C23-C26.9 Malignant neoplasm of gallbladder, other parts of biliary tract, pancreas, other digestive organs
C30.0-C49.9 Malignant neoplasm of respiratory and intrathoracic organs, bone and articular cartilage, skin, mesothelial and soft tissue
C50.011-C68.9 Malignant neoplasm of breast, female and male genital organs and urinary tract
C73-C76.8 Malignant neoplasm of thyroid and endocrine glands, neuroendocrine tumors
C77.0-C77.9 Secondary and unspecified malignant neoplasm of lymph nodes
C78.00-C78.6 Secondary malignant neoplasm of lung, respiratory organs, intestines, retroperitoneum and peritoneum
C78.80-C78.89 Secondary malignant neoplasm of other digestive organs
C79.00-C79.2 Secondary malignant neoplasm of kidney, bladder and other urinary organs, and skin
C79.51-C80.2 Secondary malignant neoplasm of other sites, and without specification of site
C81.00-C96.9 Malignant neoplasms of lymphoid, hematopoietic and related tissue
D00.00-D01.49 Carcinoma in situ of oral cavity, esophagus, stomach, colon, intestine
D01.7-D01.9 Carcinoma in situ of other digestive organs
D02.0-D09.9 Carcinoma in situ all other sites
   
References

Peer Reviewed Publications:

  1. Bakke A, Göthlin JH, Haudaas SA, Kalland T. Augmentation of natural killer cell activity after arterial embolization of renal carcinomas. Cancer Res. 1982; 42(9):3880-3883.
  2. Bercin S, Muderris T, Sevil E, et al. Efficiency of preoperative embolization of carotid body tumor. Auris Nasus Larynx. 2015; 42(3):226-230.
  3. Emori M, Kaya M, Sasaki M, et al. Pre-operative selective arterial embolization as a neoadjuvant therapy for proximal humerus giant cell tumor of bone: radiological and histological evaluation. Jpn J Clin Oncol. 2012; 42(9):851-855.
  4. Eustatia-Rutten CF, Romijn JA, Guijt MJ, et al. Outcome of palliative embolization of bone metastases in differentiated thyroid carcinoma. J Clin Endocrinol Metab. 2003; 88(7):3184-3189.
  5. Ginat DT, Saad WE, Turba UC. Transcatheter renal artery embolization for management of renal and adrenal tumors. Tech Vasc Interv Radiol. 2010; 13(2):75-88.
  6. Hosalkar HS, Jones KJ, King JJ, Lackman RD. Serial arterial embolization for large sacral giant-cell tumors: mid- to long-term results. Spine (Phila Pa 1976). 2007; 32(10):1107-1115.
  7. Koike Y, Takizawa K, Ogawa Y, et al. Transcatheter arterial chemoembolization (TACE) or embolization (TAE) for symptomatic bone metastases as a palliative treatment. Cardiovasc Intervent Radiol. 2011; 34(4):793-801.
  8. Li, J, Wang, S, Zee, C, et al. Preoperative angiography and transarterial embolization in the management of carotid body tumor: a single-center 10-year experience. Neurosurgery. 2010; 67 (4):941-948.
  9. Lin PP, Guzel VB, Moura MF, et al. Long-term follow-up of patients with giant cell tumor of the sacrum treated with selective arterial embolization. Cancer. 2002; 95(6):1317-1325.
  10. Liu WG, Gu WZ, Zhou YB, et al. The prognostic relevance of preoperative transcatheter arterial chemoembolization (TACE) and PCNA/VEGF expression in patients with Wilms tumour. Eur J Clin Invest. 2008; 38(12):931-938.
  11. Maxwell NJ, Saleem Amer N, Rogers E. Renal artery embolisation in the palliative treatment of renal carcinoma. Br J Radiol. 2007; 80(950):96-102.
  12. May M, Brookman-Amissah S, Pflanz S, et al. Pre-operative renal arterial embolisation does not provide survival benefit in patients with radical nephrectomy for renal cell carcinoma. Br J Radiol. 2009; 82(981):724-731.
  13. Nurmi M, Satokari K, Puntala P. Renal artery embolization in the palliative treatment of renal adenocarcinoma. Scand J Urol Nephrol. 1987; 21(2):93-96.
  14. Onishi H, Kaya M, Wada T, et al. Giant cell tumor of the sacrum treated with selective arterial embolization. Int J Clin Oncol. 2010; 15(4):416-419.
  15. Ramon, J, Rimon, U, Garniek, A, et al. Renal angiomyolipoma: lung-term results following selective arterial embolization, Eur Urol. 2009; 55(5): 1155-1161.
  16. Vogl TJ, Lehnert T, Zangos S, et al. Transpulmonary chemoembolization (TPCE) as a treatment for unresectable lung metastases. Eur Radiol. 2008; 18(11):2449-2455.
  17. Yang HL, Chen KW, Wang GL, et al. Pre-operative transarterial embolization for treatment of primary sacral tumors. J Clin Neurosci. 2010; 17(10):1280-1285.
  18. Zielinski H, Szmigielski S, Petrovich Z. Comparison of preoperative embolization followed by radical nephrectomy with radical nephrectomy alone for renal cell carcinoma. Am J Clin Oncol. 2000; 23(1):6-12.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. NCCN Clinical Practice Guidelines in Oncology® (NCCN). © 2017 National Comprehensive Cancer Network, Inc. For additional information: http://www.nccn.org/index.asp. Accessed on March 21, 2017.
    • Bone Cancer (V2.2016). Revised November 7, 2016.
    • Kidney Cancer (V2.2016). Revised  October 31, 2016.
    • Pancreatic Adenocarcinoma (V2.2015). Revised February 24, 2017.
    • Soft Tissue Sarcoma (V2.2016). Revised February 8, 2017.
    • Thyroid Carcinoma (V2.2015). Revised July 6, 2016.
Websites for Additional Information
  1. National Cancer Institute (NCI). Cancer Topics. Available at: https://www.cancer.gov/about-cancer .  Accessed on March 20, 2017.
Document History
Status Date Action
Revised 05/04/2017 Medical Policy & Technology Assessment Committee (MPTAC review).
Revised 05/03/2017 Hematology/Oncology Subcommittee review. Made minor typographical revision in the Position Statement section. Updated References section.
Reviewed 05/05/2016 MPTAC review.
Reviewed 05/04/2016 Hematology/Oncology Subcommittee review. Updated Rationale, References and Websites for Additional Information sections. Removed ICD-9 codes from Coding section.
Reviewed 05/07/2015 MPTAC review.
Reviewed 05/06/2015 Hematology/Oncology Subcommittee review. Updated Description, Rationale, and Websites for Additional Information sections.
Reviewed 05/15/2014 MPTAC review.
Reviewed 05/14/2014 Hematology/Oncology Subcommittee review. Updated Rationale, Background, Definitions, References, and Websites for Additional Information sections.
  01/01/2014 Updated Coding section with 01/01/2014 CPT changes; removed 37204 deleted 12/31/2013, and 75894.
Revised 05/09/2013 MPTAC review.
Revised 05/08/2013 Hematology/Oncology Subcommittee review. Minor format change/clarification to the Position Statement. Updated Rationale, Background, Definitions, and References. Added Websites for Additional Information. Removed Index.
Reviewed 05/10/2012 MPTAC review.
Reviewed 05/09/2012 Hematology/Oncology Subcommittee review. Title changed to exclude CNS and spinal cord lesions. Rationale and References updated.
Reviewed 05/19/2011 MPTAC review.
Reviewed 05/18/2011 Hematology/Oncology Subcommittee review. Description, Rationale and References updated.
New 02/17/2011 MPTAC review. Initial document development.