Coverage Policy Manual
Policy #: 2002015
Category: Radiology
Initiated: August 2002
Last Review: January 2022
  PET or PET/CT for Carcinoma of Unknown Primary (CUP)

Description:
Note:  This policy is intended for those members with contracts that do not have requirements for prior approval for imaging procedures through an independent imaging review organization.
 
“PET scan” refers to FDG PET or PET/CT.
 
Positron Emission Tomography (PET) imaging uses radiotracers that can reveal both anatomical and physiological information.  There are few radioisotopes that are approved by the FDA for PET imaging.  A radioisotope that is not FDA approved cannot be marketed; however, radioisotopes can be manufactured and used, without FDA approval, at the site of manufacture.  The FDA approved PET radioisotope, 18 Fluoro-1-deoxy-D-glucose (FDG), which is used for most oncologic imaging, including carcinoma of undetermined primary (CUP) is addressed in this policy for the following indications:
 
Carcinoma of unknown primary (CUP) represents a heterogeneous group of metastatic malignancies for which no primary tumor site can be identified after extensive diagnostic workup.  Failure to identify the primary site has been attributed to negatively impact patient management.  Evaluation of PET for CUP has been divided into two categories: 1) CUP in lymph nodes of the cervical area (Head & Neck), and 2) CUP of any area below the cervical region.
 
Definitions
 
Screening – testing in the absence of an established or clinically suspected diagnosis
 
Diagnosis - testing based on a reasonable clinical suspicion of a particular condition or disorder
 
Diagnostic Workup – initial staging of documented malignancy
 
Management – testing to direct therapy of an established condition, which may include preoperative or postoperative imaging, or imaging performed to evaluate the response to nonsurgical intervention. In oncologic imaging, management applies to patients with measurable disease and to imaging performed before or after planned treatment intervention, therapy response, restaging or clinically suspected recurrence.
 
Surveillance – periodic assessment following completion of therapy. In oncologic imaging, surveillance applies to asymptomatic patients in remission and/or without measurable disease
 
Cannot be performed or is nondiagnostic – applies when the test:
    • Is positive or indeterminate for clinically significant pathology when the information provided about the abnormality by the test is not sufficient to direct subsequent management
    • Is negative when the negative likelihood ratio of the test is both insufficient to confidently exclude the absence of suspected disease and unable to direct subsequent management. This typically applies in scenarios with moderate to high clinical pretest probability with negative testing or low pretest probability with clear evidence for net benefit
    • Has been previously nondiagnostic because of a persistent clinical factor (e.g., body habitus, immobility) that is very likely to make retesting nondiagnostic as well Cannot be performed due to a medical contraindication (e.g., contrast nephrotoxicity, allergy, or in highly radiation sensitive populations such as pediatrics and pregnancy) or reasonable unavailability related to lack of local expertise or service availability
Standard or conventional imaging: Refers to imaging that does not require a PET/CT. Depending
on the clinical scenario and individual patient circumstances, this may include computed tomography, magnetic resonance imaging, ultrasound and/or scintigraphy.
 

Policy/
Coverage:
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
FDG-PET/CT for patients with Cancers of Unknown Primary and Cancers Not Otherwise Specified meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for patients for:
Diagnostic Workup:
      • Indicated when standard imaging cannot be performed or is nondiagnostic in determining the extent of disease
Management:
      • Indicated when standard imaging cannot be performed or is nondiagnostic in determining the extent of disease  
 
* For fully-insured contracts subject to Act 583 of Arkansas legislature, please see ABCBS policy 2021004, Surveillance and Other PET Oncologic Applications.
 
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
PET/CT for patients with Cancers of Unknown Primary does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for any other indication not listed as covered above including but not limited to:  
    • Surveillance*
For contracts without primary coverage criteria, PET/CT for patients with Cancers of Unknown Primary is considered investigational and is not covered for any indication or any circumstance other than those listed above including but not limited to:  
    • Surveillance*
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
* For fully-insured contracts subject to Act 583 of Arkansas legislature, please see ABCBS policy 2021004, Surveillance and Other PET Oncologic Applications.
 
 
Note: Standard or conventional imaging: Refers to imaging that does not require a PET/CT. Depending on the clinical scenario and individual patient circumstances, this may include computed tomography, magnetic resonance imaging, ultrasound and/or scintigraphy.
 
 
Effective Prior to March 13, 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
FDG-PET/CT for patients with Cancers of Unknown Primary meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for:
 
Diagnostic Workup
Indicated when standard imaging cannot be performed or is nondiagnostic in determining the extent of disease.
 
Treatment Management
Indicated when standard imaging cannot be performed or is nondiagnostic in determining the extent of disease.
 
For fully-insured contracts subject to Act 583 of Arkansas legislature, please see ABCBS policy 2021004, Surveillance and Other PET Oncologic Applications.
 
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
PET/CT for patients with Cancers of Unknown Primary does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for:
    • For screening and surveillance* or
    • For any other indication not specifically listed above.
 
*For fully-insured contracts subject to Act 583 of Arkansas legislature, please see ABCBS policy 2021004, Surveillance and Other PET Oncologic Applications.
 
For members with contracts without primary coverage criteria, PET/CT for patients with Cancers of Unknown Primary is considered investigational for:  
    • For screening and surveillance; or
    • For any other indication not specifically listed above.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
 
Effective Prior to August 2021
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
FDG-PET/CT for patients with Cancers of Unknown Primary meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for:
 
Diagnostic Workup
Indicated when standard imaging cannot be performed or is nondiagnostic in determining the extent of disease.
 
Treatment Management
Indicated when standard imaging cannot be performed or is nondiagnostic in determining the extent of disease.
 
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
PET/CT for patients with Cancers of Unknown Primary does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for:
    • For screening and surveillance or
    • For any other indication not specifically listed above.
For members with contracts without primary coverage criteria, PET/CT for patients with Cancers of Unknown Primary is considered investigational for:  
    • For screening and surveillance; or
    • For any other indication not specifically listed above.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective Prior to June 15, 2021
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
PET scan imaging as an aid in detection and initial staging of the primary site of tumor in patients with carcinoma of unknown primary metastatic to cervical nodes meets member certificate of benefit Primary Coverage Criteria for effectiveness.
 
PET scan imaging for restaging of carcinoma of unknown primary metastatic to cervical nodes meets member certificate of benefit Primary Coverage Criteria for effectiveness assuming the tumor is FDG-avid.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
PET scan imaging as an aid in detection of primary site of tumor in patients with extracervical carcinoma of unknown primary does not meet member certificate of benefit Primary Coverage Criteria based on the results of a clinical trial  (MØller, 2012), an ongoing clinical trial (NCT01469026), and NCCN Guidelines (Version 1.2013).
 
For members with contracts without primary coverage criteria, PET scan imaging as an aid in detection of primary site of tumor in patients with extracervical carcinoma of unknown primary is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
PET scan imaging for surveillance of carcinoma of unknown primary metastatic to cervical nodes does not meet member certificate of benefit Primary Coverage Criteria for effectiveness based on lack of evidence of effectiveness and Expert Opinion (Podoloff, 2009; NCCN Guidelines on surveillance PET scan imaging)
 
For members with contracts without primary coverage criteria, PET scan imaging for surveillance of carcinoma of unknown primary metastatic to cervical nodes is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
PET scan imaging for monitoring of carcinoma of unknown primary of any site does not meet member certificate of benefit Primary Coverage Criteria for effectiveness based on lack of evidence of effectiveness, and Expert Opinion (Podoloff, 2009; NCCN Guidelines on monitoring with PET scan imaging).
 
For members with contracts without primary coverage criteria, PET scan imaging for monitoring of carcinoma of unknown primary of any site is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 

Rationale:
NCCN Clinical Guidelines, Head & Neck Cancer/Occult Primary.  Version 1.2012.  www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf  Accessed 2012-10-30
 
NCCN Clinical Guidelines, Occult Primary.  Version 1.2013.  www.nccn.org/professionals/physician_gls/pdf/occult/pdf  Accessed 2012-10-30
For initial evaluation, NCCN deleted a previous “2B” recommendation for PET/CT, and present guidelines state, “Routine use of PET/CT is not recommended.  PET/CT may be warranted in some situations.”
 
Canadian Agency for Drugs and Technologies in Health (Mujoomdar, 2010)
The April 2010 Canadian Agency for Drugs and Technologies in Health assessment of PET in Oncology does not include an assessment of PET for carcinoma of unknown primary.  
                             
NCCN Task Force Report (Podoloff DA, 2009)  
The Podoloff, et al review does not address carcinoma of unknown primary.
 
Expert Panel Review (Fletcher, et al, 2008)
“The panel concluded that 18F-FDG PET should routinely be added to the conventional work-up or patients with unknown primary cancer.”  This decision was based on 2 systematic reviews enrolling a total of 298 and 302 patients, with over 50% of the Delgado-Bolton study being patients with cervical node cancer, and all of the Rusthoven paper being patients with cervical lymph node metastases.  
 
National Oncologic PET Registries Reports, 2008, 2009, and 2011 (Hillner, 2008, 2009, 2011)
None of these studies addresses carcinoma of unknown primary
 
AHRQ University of Alberta Evidence Based Practice Center assessment (2008)
No discussion of carcinoma of unknown primary
 
Specific Study: A Prospective Comparison of 18F-FDG PET/CT and CT as Diagnostic Tools to Identify the Primary Tumor Site in Patients with Extracervical Carcinoma of Unknown Primary Site (MØeller, 2012).  136 newly diagnosed CUP patients with extracervical metastases underwent FDG PET/CT, and compared to a standard of reference and CT.  Standard of reference identified a primary tumor site in 66 CUP patients (48.9%).  PET/CT identified 38 true positive tumor sites and CT identified 43 true positive primary tumor sites.  No statistically significant differences were observed between 18F-FDG PET/CT and CT alone in regard to sensitivity, specificity, and accuracy.
 
Specific Study: 18F-FDG PET/CT as a Diagnostic Tool in Patients with Extracervical Carcinoma of Unknown Primary Site: A Literature Review (Moller AKH, 2011).  This review found 4 publications involving 152 patients which evaluated 18F-FDG PET/CT in CUP patients with extracervical metastases.  All studies were retrospective and heterogeneous in inclusion criteria, study design, and diagnostic workup prior to 18F-FDG PET/CT.  PET/CT detected the primary tumor in 39.5% of patients with extracervical CUP.  The most frequent site of the primary was in the lung.  The pooled estimates of sensitivity, specificity, and accuracy of PET/CT with FDG in detection of the primary site were 8%, 88%, and 87.5%, respectively.  The authors concluded, “The present review of currently available data indicates that 18F-FDG PET/CT might contribute to the identification of the primary tumor site in extracervical CUP.  However, prospective studies with more uniform inclusion criteria are required to evaluate the exact role of this diagnostic tool.”
 
Specific Study: Clinical Applications of FDG PET and PET/CT in Head and Neck Cancer (Al-Ibraheem A, 2009).  This meta-analysis of PET/CT in head & neck cancer included an analysis of CUP in cervical nodes in studies published between 2000-2009.  PET & PET/CT detected the primary tumor in 51 of 180 patients.  There were 30 false positives.  PET alone was not distinguished from PET/CT.
 
Specific Study: The role of fluorodeoxyglucose positron emission tomography in cervical lymph node metastases from an unknown primary tumor (Rusthoven KE, 2004).  This was a review of 302 patients (PET scan imaging only) described in 16 studies published between 1994 and 2003.  18F-FDG PET detected 24.5% of tumors that were not apparent after conventional workup.
 
2013 Update
A search of the MEDLINE database through October 2013 did not reveal any new literature that would prompt a change in the coverage statement.
 
Cizmarevic and colleagues published the results of a study done to determine the survival rate of patients with carcinoma of unknown primary (CUP) in relation to lymph node status and eventual later identification of the primary tumor and to investigate the impact of PET-CT on identification of the primary tumor (Cizmarevic, 2012).  This study included 97 patients with diagnosis of metastasis of unknown primary tumor.  All susceptible patients had a surgery and postoperative radiation therapy.  After treatment was completed they were followed up at ENT department.  With preoperative examinations 48 primary tumors were discovered.  Only in one case of 13 the PET-CT detected the primary tumor not confirmed with other examination methods.  After the treatment primary tumors we found were found in 10 patients. In 39 patients we didn't discover any primary tumor.  The authors concluded that PET-CT method was not particularly useful in detecting primary tumors in patients with metastasis with unknown primary.
 
Ongoing Clinical Trials
    • NCT01469026 – “The Value of Early PET/CT in Patients With Metastasizing Cancer of Unknown Primary”; planned in 2011 with an estimated enrollment of 220 and completion date of 12/2014.  NCT site has not been updated since 11/2011.
 
2014 Update
 
A literature search conducted through October 2014 did not reveal any new information that would prompt a change in the coverage statement.
 
2015 Update
 
A literature search conducted through January 2015 did not reveal any new information that would prompt a change in the coverage statement
 
2018 Update
Annual policy review completed with a literature search using the MEDLINE database through February 2018. No new literature was identified that would prompt a change in the coverage statement.
 
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through February 2019. No new literature was identified that would prompt a change in the coverage statement.
 
2020 Update
A literature search was conducted through February 2020.  There was no new information identified that would prompt a change in the coverage statement.  
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through January 2021. No new literature was identified that would prompt a change in the coverage statement.
 
2022 Update
A literature review was performed through September 2021. Following is a summary of the key literature to date.
 
DIAGNOSTIC WORKUP
For malignancy of unknown origin involving the cervical lymph nodes but suspected to be of Head/Neck origin, please see “Head and Neck Cancer” coverage policy and guidelines.
 
The initial work-up for cancers of unknown primary should include a history and physical, laboratory evaluation, and imaging studies. CT of the chest, abdomen, and pelvis is commonly used to identify the primary cancer, assess extent of disease, and select for sites amenable to biopsy. (3)  PET imaging is increasingly being used as part of the diagnosis of CUP. A meta-analysis and systematic review on the use of PET/CT in patients with CUP found that primary tumors were detected in 37% of 433 patients from 11 studies, with pooled sensitivity and specificity both at 84%. (4) Another study found that PET/CT detected more primary sites (24%-40%) than CT or MRI (20%-27%). (5) NCCN, however, does not recommend routine use of PET imaging for CUP due to a lack of prospective randomized studies comparing PET imaging to conventional imaging. (6) Special consideration should be given to patients presenting with a solitary metastasis where localized intervention is planned and to cervical nodal metastases of unknown origin. In a comprehensive review of patients with a solitary metastasis, PET imaging changed management in 34% of patients relative to conventional imaging. Fourteen percent of patients underwent surgery with curative intent. (7) In a systematic review and meta-analysis of patients with cervical nodal metastases of unknown origin, the primary tumor detection rate, sensitivity, and specificity of PET-CT were 0.44 (95% CI, 0.31-0.58), 0.97 (95% CI, 0.63-0.99), and 0.68 (95% CI,0.49-0.83). Area under the curve was 0.83 (95% CI, 0.80-0.86). (8) The initial work-up of patients with cancer not otherwise specified should include imaging of the primary neoplastic process and assessment for systemic involvement if warranted. Specific imaging recommendations vary with underlying pathologic diagnosis, staging, and patient factors. Because of the many nuances associated with cancer evaluation, peer-to-peer discussions will often be necessary to determine appropriateness of advanced imaging.
 
MANAGEMENT
For patients with either active disease or localized disease in remission, follow-up frequency should be determined by clinical need with additional diagnostic tests based on symptomatology. (6) Subsequent imaging strategy for cancer not otherwise specified varies with underlying pathologic diagnosis and staging. In general terms, imaging used in the initial detection of the cancer may be used to assess for treatment response.
 
SURVEILLANCE
For patients with either active disease or localized disease in remission, follow-up frequency should be determined by clinical need with additional diagnostic tests based on symptomatology. (6) The type and frequency of surveillance imaging for cancer not otherwise specified is dependent on the underlying pathologic diagnosis and staging. When indicated, CT imaging can be used in most cancers, with PET rarely indicated for surveillance.
 
Current References
    1. Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2021. CA Cancer J Clin. 2021;71(1):7-33. PMID: 33433946
    2. Losa F, Soler G, Casado A, et al. SEOM clinical guideline on unknown primary cancer (2017). Clin Transl Oncol. 2018;20(1):89-96. PMID: 29230692
    3. Kim KW, Krajewski KM, Jagannathan JP, et al. Cancer of unknown primary sites: what radiologists need to know and what oncologists want to know. AJR Am J Roentgenol. 2013;200(3):484-92. PMID: 23436835
    4. Kwee TC, Kwee RM. Combined FDG-PET/CT for the detection of unknown primary tumors: systematic review and meta-analysis. Eur Radiol. 2009;19(3):731-44. PMID: 18925401
    5. Ambrosini V, Nanni C, Rubello D, et al. 18F-FDG PET/CT in the assessment of carcinoma of unknown primary origin. Radiol Med (Torino). 2006;111(8):1146-55. PMID: 17171520
    6. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Occult Primary (Cancer of Unknown Primary [CUP]) (Version 2.2021). Available at http://www.nccn.org. ©National Comprehensive Cancer Network, 2021.
    7. Seve P, Billotey C, Broussolle C, et al. The role of 2-deoxy-2-[F-18]fluoro-D-glucose positron emission tomography in disseminated carcinoma of unknown primary site. Cancer. 2007;109(2):292-9. PMID: 17167760
    8. Zhu L, Wang N. 18F-fluorodeoxyglucose positron emission tomography-computed tomography as a diagnostic tool in patients with cervical nodal metastases of unknown primary site: a meta-analysis. Surg Oncol. 2013;22(3):190-4. PMID: 23849685
 

CPT/HCPCS:
78811Positron emission tomography (PET) imaging; limited area (eg, chest, head/neck)
78812Positron emission tomography (PET) imaging; skull base to mid thigh
78813Positron emission tomography (PET) imaging; whole body
78814Positron emission tomography (PET) with concurrently acquired computed tomography (CT) for attenuation correction and anatomical localization imaging; limited area (eg, chest, head/neck)
78815Positron emission tomography (PET) with concurrently acquired computed tomography (CT) for attenuation correction and anatomical localization imaging; skull base to mid thigh
78816Positron emission tomography (PET) with concurrently acquired computed tomography (CT) for attenuation correction and anatomical localization imaging; whole body

References: Al-Ibraheem A, Buck A, Krause BJ, et al.(2009) Clinical applications of FDG PET and PET/CT in head and neck cancer. J of Oncology, 2009.

BE Hillner, BA Siegel. Hanna L, et al.(2012) Impact of 18F-FDG PET used after initial treatment of cancer: comparison of the Nationl Oncologic PET Registry 2006 and 2009 cohorts. J Nucl Med, 2012; 53:831-837.

Cizmarevic B, Lanisnik B, Dinevski D.(2012) Cervical lymph node metastasis of squamous cell carcinoma from unknown primary tumor. Coll Antropol. 2012 Nov;36 Suppl 2:27-32.

Delgado-Bolton RC, Fernández-Pérez C, González-Maté A, et al.(2003) Meta-analysis of the performance of 18F-FDG PET in primary tumor detection in unknown primary tumors. J Nucl Med, 2003; 44:1301-1314.

Fletcher JW, Djulbegovic B, Soares HP, et al.(2008) Recommendations on the Use of 18F-FDG PET in Oncology. J Nucl Med, 2008; 49:480-508.

Hillner BE, Siegel BA, Shields AF, et al.(2008) Relationship between cancer type and impact of PET and PET/CT on intended management: Findings of the National Oncologic PET Registry. J Nucl Med, 2008; 49:1928-1935.

Hillner BE, Siegel BA, Shields AF, et al.(2009) The impact of positron emission tomography (PET) on expected management during cancer treatment. Cancer, 2009; 115:410-418.

Moller AK, Loft A, Berthelsen AK, et al.(2011) 18F-FDG PET/CT as a diagnostic tool in patients with extracervical carcinoma of unknown primary site: A literature review. The Oncologist, 2011; 16:445-451.

Møller AK, Loft A, Berthelsen AK, et al.(2012) A prospective comparison of 18F-FDG PET/CT and CT as diagnostic tools to identify the Primary Tumor Site in Patients with extracervical carcinoma of unknown primary site. Oncologist. 2012;17(9):1146-54.

Mujoomdar M, Moulton K, Nkansah E.(2010) Positron emission tomography (PET) in oncology: A systematic review of clinical effectiveness and indications for use. Canadian Agency for Drugs and Technologies in Health, April 2010.

NCCN Guidelines.(2013) Occult Primary, Version 1.2013. www.nccn.org/professionals/physician_gls/pdf/occult. Accessed 2012-10-30.

NCT00530283.(2012) PET-CT for squamous cell carcinoma of the neck nodes unknown primary. Alberta Health Services. Completed, not yet reported. www.clinicaltrials.gov.Accessed 2012-10-30

NCT01469026.(2012) CUP project PET/CT. Odense University Hospital. Not yet open for participant recruitment. www.clinicaltrials.gov.Accessed 2012-10-30

Podoloff DA, Ball DW, Ben-Josef E, et al.(2009) NCCN task force report: clinical utility of PET in a variety of tumor types. JNCCN, 2009; 7 Suppl 2:S1-S23.

Rusthoven KE, Koshy M, Paulino AC.(2004) The role of fluorodeoxyglucose positron emission tomography in cervical lymph node metastases from an unknown primary tumor. Cancer, 2004; 101:2641-2649.


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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