The use of PET/CT scan in Oncology – OEK – KY.E.P.I. – PEK – AEK – May 2022

This study is a product of collaboration between the Cyprus Oncology Society (OEK), the Cyprus Society of Nuclear Medicine (KY.EPI), the Cyprus Paediatric Society (PEK) and the Cyprus Radiological Society (AEK). It is signed by the representatives of the Scientific Societies in the Joint Technical Committee of PIS-OAY for the promotion and implementation of protocols and clinical guidelines and aims to guide clinicians in the use of PET/CT scan in Oncology. Publication date: 18 May 2022.

The use of PET/CT scan in Oncology

Katodrytis N ¹ , Vrachimis A ² , Dimitriadou O ² , Frangos S ² , Konstantinidou A ¹ , Drakos P ¹ , Ferentinos K ¹ , Bombas D ¹ , Giallouros P ³ ,

Elias A ³ ,  Savva S ³ ,  Anastasiadis M ³ , Orphanidou E ⁴ , Zouvanni M ⁴ , Symeonidou X ⁴ , Tsiskaris M ⁴ , Kourri A ⁴ , Tziakouris X ⁴

¹ Cyprus Oncological Society (OEK), ²  Cyprus Society of Nuclear Medicine (KY.E.P.I.),        ³ Cyprus Paediatric Society (PEK), ⁴ Cyprus Radiological Society (AEK)   

Import

The nuclear medicine examination Positron Emission Tomography (PET-Scan) in combination with Computed Tomography (PET/CT scan) is an important diagnostic examination. The role of PET/CT has been established in Oncology with specific indications and its clinical application is broad.[1] It is a non-invasive diagnostic examination that offers tomographic imaging and can be used to calculate quantitative parameters regarding the metabolic activity of tissues.{2} The radiopharmaceutical 18F-FDG, which is the most commonly used, has high sensitivity but lacks specificity for specific types of cancer and/or organs. The examination has the advantage of being able to image the entire body. [1,2]

The role of PET/CT in Oncology has undoubtedly expanded over the last 10 years and the examination is performed in a significant number of common cancers.[1]

Purpose

The purpose of the study is to document the indications for the application of PET/CT in Oncology through a review of the international literature. The documentation could serve as a recommendation to clinicians for performing the examination.

Method

The European Agency for Nuclear Medicine (EANM) Guidelines published in 2015 in the European Journal of Nuclear Medicine and Molecular Imaging, the Royal College of Physicians Guidelines published in 2012 in the Clinical Medicine (Lond), the AIM Specialty Health Guidelines published in 2017 and the HAL Good clinical practice recommendations for the use of PET/CT in oncology, a joint effort of the French National Health Authority (HAS) and the French Cancer Institute (INCa) and in collaboration with the French Society for Nuclear Medicine (SFMN) published in 2020 in the European Journal of Nuclear Medicine and Molecular Imaging, were reviewed. The National Comprehensive Cancer Network (NCCN-Clinical Practice Guidelines in Oncology) were also taken into account.

In addition, the revised 2021 oncological indications for PET of the European Organization for Nuclear Medicine (EANM) were studied and have been incorporated into the CDS tool (software), which aims to provide Nuclear Medicine physicians with scientifically documented guidance to identify the most appropriate nuclear medicine examinations in each case. The Guidelines are also of great value for referring physicians to identify the most appropriate examinations for their patients in each case.

Finally, the recommendations of the Society of Nuclear Medicine and Molecular Imaging (SNMMI) and the European Association of Nuclear Medicine (EANM) for the indications for the application of 18F-FDG-PET/CT in Pediatric Oncology, which were published in 2021 in The Journal of Nuclear Medicine, were studied. In addition, the guidelines Guidelines for the use of PET/CT in children, Second Edition, The Royal College of Radiologists were taken into account.

The recommendations listed are based on scientific documentation (evidence based) of Level A and B (Level of Evidence), namely [4]:

• Level A: There is a good quality meta-analysis or good quality randomized trials with cross-over results. Any new data will most likely not change the confidence in the expected result.
• Level of evidence B: There is good quality evidence (randomized studies or prospective or retrospective studies with cross-over results or good quality randomized studies with cross-over results). Any new data may affect the degree of confidence in the expected result or even change it.   

Regarding the degree of recommendation, it should be noted that where it is stated “recommended” it is understood that it is the ” clinical reference standard” and where it is stated “can be performed” it is understood that it is acceptable on the basis of bibliographic references without being unanimously recognized as a “clinical reference standard”.

Recommendations for adult cases

In general, PET/CT examination is applied in Oncology in the following cases [1,2,7]:

• Differentiation between benign and malignant anatomical lesions
• Primary tumor localization in patients presenting with metastases
• Disease staging
• Evaluation of response to treatment
• Local recurrence
• Disease progression assessment
• Selecting an accessible lesion for biopsy
• Radiotherapy Planning

In detail, the 18F-FDG-PET/CT examination is recommended in the following cases. The indications for the level of scientific documentation (Level of Evidence) A and B are recorded:

Lung Cancer

18F-FDG-PET/CT  
is recommended in the initial staging of NSCLC to exclude distant metastases and to avoid surgery in patients who are candidates for radical treatment including chemoradiotherapy. In addition, for staging of mediastinal lymph nodes and possible biopsy for confirmation of lymph node disease. In addition, the examination can be performed for restaging, confirmation or exclusion of suspected recurrence after radical treatment.[1,3,5,7]

Comment: Approximately 10% of patients may present with distant metastases not detected by conventional imaging methods.

It is also recommended for the investigation of a solitary nodule in the lung since it exhibits high sensitivity (sensitivity around 95%) in the characterization of pulmonary nodules >8mm in size. [3,4,7]

Comment: A meta-analysis of 13 studies with 450 patients reported a sensitivity and specificity of 18F-FDG-PET/CT in solitary pulmonary nodules of 92.4% and 83.3%, respectively. False-positive results may occur in inflammatory or granulomatous lesions. [1]  

In addition, it can be performed to stage NSCLC before administering radical treatment (Limited Disease).[4,5]

Finally, 18F-FDG-PET/CT can be performed for radiotherapy planning, especially in patients with atelectasis.[4,7]

Lymphoma, Multiple Myeloma and Plasmacytoma

18F-FDG-PET/CT is recommended for the initial diagnosis and staging of lymphoma, as well as for the evaluation of treatment outcome and suspected recurrence. [1,3,4,7]

In multiple myeloma, it is recommended for staging, assessment of response to treatment, especially in patients who are candidates for autologous bone marrow transplantation and in cases of suspected relapse.[7]

It is also recommended in the initial staging of plasmacytoma and in response to treatment.[7]

Head and Neck Cancer

18F-FDG-PET/CT is recommended for the staging of locally advanced stages of squamous cell carcinoma, i.e. stages T3-4, N1-3, assisting both in local evaluation and in the exclusion of distant metastases, while 
it can be performed to exclude a concomitant second cancer of the Head and Neck region.[3,4,7]

It is also recommended for post-treatment monitoring of residual disease or detection of recurrence, as well as for the detection of the primary tumor in cases with metastatic lymphadenopathy of unknown primary tumor.[1,4,5,7]

It is also recommended for the staging of nasopharyngeal carcinomas [4,5], including undifferentiated carcinomas [7], while it is not recommended for the characterization of cases with salivary gland cancer or nasal and paranasal cavities, but it can be performed for initial staging purposes.[4]

Finally, it can be performed for radiotherapy planning purposes. [3,4]

Cancer of Unknown Primary   Tumour (CUP)

18F-FDG-PET/CT is recommended  for the investigation/localization of the primary tumor in cases of diagnosis of metastatic cervical lymphadenopathy of unknown primary tumor, but also for the identification of a representative lesion suitable/accessible for biopsy.[1,4,5,7]

Colorectal Cancer, Gastrointestinal Tract

18F-FDG-PET/CT is recommended for pre-treatment screening, especially if there is suspicion of the presence of distant metastases.[3,4,7]  

Comment: Negative conventional staging is sufficient for treatment.[3,4]

In colorectal cancer, it is recommended for investigation of suspected recurrence, especially where an isolated increase in Carcinoembryonic Antigen (CEA) is observed.[7]

In anal cancer, it is recommended in the staging stages T2-T4N0 and in N+. [7]

In esophageal cancer , 18F-FDG-PET/CT is recommended before radical treatment (surgery, chemoradiotherapy).[4,7]

Furthermore, it can be performed to assess response to treatment, to develop a treatment plan, and to detect suspected relapse.[7]

In stomach and pancreatic cancer, it can be performed  for staging but also in cases of suspected recurrence.[7]

In gallbladder cancer, it may be performed  for staging.[7]

Breast, Urinary System and Gynecological Cancer

18F-FDG-PET/CT is not included in routine examinations for breast, urinary tract and gynecological cancers.

It may be performed  to detect recurrence or metastatic disease if there is strong clinical suspicion with negative conventional imaging tests.[1,3,4]

In breast cancer, it can be performed in staging stages >IIB, preferably before surgery.[7]

Especially in ovarian cancer, it is recommended for investigating suspected recurrence, especially where an isolated increase in Cancer Antigen 125 (Ca-125) is observed, while it can be performed   for the staging of recurrence.[7]

In testicular cancer, it can be performed in staging, to check the response to treatment, and in case of suspected recurrence.[7]

It is recommended for differentiating between benign and malignant adrenal lesions, as well as in the staging of adrenal cancer (Adrenal Cortex Carcinoma).[7]

Prostate Cancer

The indicated test is PSMA (Prostate Specific Membrane Antigen).[4,7]

Comment: Literature data report better sensitivity of PSMA compared to 18F/11C-choline.[4,7]

The test is not recommended for intraprostatic lesions.[4]

PSMA is recommended  for the investigation of biological recurrence. Its use is recommended (but not limited) especially in patients with low PSA values ​​(between 0.2 and 10 ng/mL) to identify the site of recurrence and perhaps to aid in the decision to administer salvage therapy.{7}

Comment: Greater sensitivity is noted in patients with shorter PSA doubling times and in those with higher initial Gleason scores.[7]

PSMA PET/CT (if this is not available, Choline-PET/CT) can be performed to stage high-risk patients (ISUP 3, ISUP 4 and ISUP 5) before radical treatment.[4]

Melanoma

In melanoma, it can be performed in stages IIIB-C and in stage IV with negative conventional staging.[4,7] 

Comment: 18F-FDG-PET/CT has been reported to have a sensitivity of 87%, while it can change therapeutic management in stage IV by 15%.[1]

18F-FDG-PET/CT is not recommended for staging stage I-II cutaneous melanoma and does not replace sentinel lymph node biopsy.[4]

It is not recommended as a routine test in the follow-up of asymptomatic patients with stages I-IIIA. It may be performed in case of suspicious clinical symptoms in high-risk patients with stages IIIB-IV.[4]

Thyroid Cancer

In well-differentiated thyroid carcinoma (papillary/follicular), 18F-FDG-PET/CT is recommended in cases of suspected dedifferentiation (especially in high thyroglobulin values ​​without correlation on iodine scintigraphy, non-iodine avid thyroid cancer).[3,7]

In poorly differentiated thyroid cancer, it is recommended for postoperative staging. [3.7]

In medullary thyroid carcinoma, it is recommended for staging and in cases of suspected recurrence.[3,7]

Osteosarcoma

18F-FDG-PET/CT can be performed for the initial evaluation of osteosarcomas. [4]

Neuroendocrine Tumors

SST PET is recommended for both initial staging and suspected recurrence.[7]

Bone metastases/Secondary sites

18F-FDG-PET/CT is recommended for metabolic evaluation, confirmation/exclusion of bone metastases/secondary foci in tumors that show increased FDG metabolism (FDG-avid tumors).[7] 

Note:

PET/CT may also be useful in clinical situations where the examination is not supported by strong scientific evidence. The decision on any benefit from performing the examination should be made by a Multidisciplinary/Interdisciplinary Oncology Board.

Pediatric Oncology

Common indications for 18F-FDG-PET/CT in Pediatric Oncology include but are not limited to the following [6,8]:

Lymphoma (Hodgkin lymphoma [HL] and non-Hodgkin lymphoma [NHL])

18F-FDG-PET/CT is recommended in the following cases [6]:

• Initial staging
• Monitoring response to treatment (monitoring during and after completion of treatment)
• Identification of residual disease
• Restaging
• Programming of the AKTH
• Obtaining information about prognosis (Clarification: Assessing the prognosis of a disease through PET is not the main reason for performing the examination, but additional information, the value of which will be assessed by the treating physician.)

18F-FDG PET/CT is not recommended as a routine examination for post-treatment monitoring purposes.

Sarcoma (osteosarcoma, Ewing’s sarcoma , rhabdomyosarcoma, and other soft tissue sarcomas)

18F-FDG-PET/CT is recommended in the following cases [6]:

• Initial staging
• Response to treatment of osteosarcoma, rhabdomyosarcoma and Ewing sarcoma
• Obtaining information about prognosis (Clarification: Assessing the prognosis of a disease through PET is not the main reason for performing the examination, but additional information, the value of which will be assessed by the treating physician.)
• Possibly for restaging and detection of recurrence

Absolute indications for performing 18F-FDG-PET/CT, and consequently its performance is recommended , are [8]:  

• Extramedullary leukemia
• Pediatric GISTs (Gastro-Intestinal Stromal Tumours)
• Malignancy with Unknown Primary

Indications with partial scientific documentation for the use of 18F-FDG PET/CT, in which it can therefore be performed  [6,7,8]:

• MIBG-negative neuroblastoma cases (pre-treatment prognostic information)
• Central Nervous System Tumors (grade of differentiation, assessment of response to treatment, prognosis and differentiation of residual disease versus post-radiation lesions after ASC)
• Head and Neck Cancers including nasopharyngeal cancer
• Langerhans Cell Histiocytosis
• Posttransplant lymphoproliferative disorder
• Germ cell tumors (staging, detection of recurrence)
• Wilms tumors
• Thyroid Cancer (negative iodine scan with rising serum thyroglobulin level)
• Neurofibromatosis Type I (if malignant mutation in neurofibroma is suspected)
• Thymic neoplasm (to evaluate the possibility of performing guided biopsy and surgical removal, planning ATC)
• Fever of unknown etiology – after other causes have been ruled out and there is a strong suspicion of malignancy.
• Opsoclonus-Myoclonus Syndrome without primary
• Congenital hyperinsulinism of infancy (CHI)

For follow- up purposes, PET/CT can only be performed in cases of relapse/exacerbation, where immediate treatment planning is needed to save life.[8]

Note:

18F-FDG PET/CT may be useful in children and in other clinical situations for which the examination is not supported by strong scientific evidence. The decision on any benefit from performing the examination should be made by a Multidisciplinary/Interdisciplinary Oncology Board.

Conclusion

PET/CT scan is an important diagnostic test in Oncology. The test is used increasingly frequently and offers significant diagnostic assistance, which can improve treatment outcomes.

The above-mentioned indications are based on scientific documentation and the recommendation to perform the examination should be validated by a Multidisciplinary/Interdisciplinary Oncology Council.

Bibliography

1. Fahim Ul-Hassan, Gary J Cook. PET/CT in oncology. Royal College of Physicians. Clin Med (Lond) 2012 Aug; 12(4): 368-372. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4952129/#!po=22.7273
2. Ronald Boellaard et al. FDG PET/CT: EANM procedure guidelines for tumor imaging:

version 2.0. Eur J Nucl Med Mol Imaging (2015) 42:328–354. https://www.eanm.org/publications/guidelines/2015_GL_PET_CT_TumorImaging_V2.pdf

3. AIM Specialty Health. Clinical Appropriateness Guidelines: Advanced Imaging.

Appropriate Use Criteria: Positron Emission Testing, Other PET Applications, including Oncologic Tumor Imaging. Last reviewed: 11/01/2016. Effective Date: September 5, 2017

4. Pierre-Yves Salaun, Ronan Abgral, Olivier Malard, Solène Querellou-Lefranc, Gilles Quere, et al. Good clinical practice recommendations for the use of PET/CT in oncology. European Journal of Nuclear Medicine and Molecular Imaging, Springer Verlag (Germany),2020,47(1),pp.28-50.
5. NCCN – Clinical Practice Guidelines in Oncology. National Comprehensive Cancer Network,  Version 7.2021 and 2.2022
6. Reza Vali, Adam Alessio, Rene Balza, Lise Borgwardt, Zvi Bar-Sever, Michael Czachowski, Nina Jehanno, Lars Kurch, Neeta Pandit-Taskar, Marguerite Parisi, Arnoldo Piccardo, Victor Seghers, Barry L. Shulkin, Pietro Zucchetta and Ruth Lim. SNMMI Procedure Standard/EANM Practice Guideline on Pediatric 18F-FDG PET/CT

for Oncology 1.0. Journal of Nuclear Medicine January 2021, 62 (1) 99-110. https://jnm.snmjournals.org/content/62/1/99

7. Clinical decision support. European Association of Nuclear Medicine (EANM) 2021. https://www.eanm.org/publicpress/nuclear-medicine-clinical-decision-support/

PET in Oncology https://www.nucmed-cds.app/#!/questions/8107

8. Guidelines for the use of PET/CT in children, Second Edition, The Royal College of Radiologists. Indications for PET/CT scan in children with known/suspected malignancy, Clinical Radiology. Date: 2014, Date of last review:2017. rcr.ac.uk , https://www.rcr.ac.uk/publication/guidelines-use-pet-ct-children-second-edition