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EAU 2024

EAU 2024: Disease Characterization: FDG-PET For Staging, Is It Mandatory?

(UroToday.com) The 2024 European Association of Urology (EAU) annual congress held in Paris, France between April 5th and 8th was host to a plenary session addressing imaging-related controversies for the staging of genitourinary cancers. Professor Sharokh Shariat discussed whether fluorodeoxyglucose (FDG)-positron emission tomography (PET) is mandatory for the staging of bladder cancer patients.


What is the future of perioperative treatment of muscle invasive bladder cancer? With the emergence of more effective systemic therapies (e.g., enfortumab vedotin + pembrolizumab), improved imaging techniques to detect residual disease in the bladder will be of increased importance. Bladder-sparing approaches in patients who have no clinical evidence of residual disease remain an important clinical goal, with patients having evidence of residual disease (either in the bladder or with subclinical, limited metastases) recommended for surgery.
Could FDG PET/CT be the answer in this setting? What are the performance characteristics of this imaging test? A 2018 meta-analysis demonstrated that FDG PET/CT, compared to conventional CT, improves the sensitivity in lymph node staging from 37% to 52%.1

Can the SUVmax values from FDG PET scans be used to predict regional nodal metastases pre-operatively? Vind-Kezunovic et al. published an analysis of 119 patients with urothelial carcinoma who underwent a radical cystectomy with an extended lymph node dissection, all of whom underwent an 18F-FDG PET/CT scan pre-operatively. In total, 2,291 nodes were identified in 131 patients; locoregional involvement of 85 lymph nodes were confirmed in 34 patients. For patients with lesions having an SUVmax >2, the sensitivity and specificity for detecting nodal involvement were 80% and 67%, respectively. When the cut-off is increased to >4, the sensitivity decreased to 62%, but the specificity increases to 85%. Two years of follow-up implied that higher SUVmax is correlated with higher recurrence risk, independent of conventional pathological findings. The authors concluded that 18F-FDG PET/CT using SUVmax of lymph nodes is a useful tool for the pre-operative evaluation of pelvic nodal metastases from invasive bladder cancer and contributes to the selection of patients for personalized treatment.2 

Is there a role for PET/CT for assessing nodal involvement in the neoadjuvant setting for patients with muscle-invasive disease? Marandino et al. evaluated 105 patients receiving neoadjuvant pembrolizumab with evaluable baseline and post-pembrolizumab scans. The sensitivity for the detection of lymph node involvement was 27% and 37.5% for pre- and post-pembrolizumab PET/CT, and specificity was 97% and 98%, respectively. In total, 4 of 7 patients (57%) showing baseline FDG-uptake had lymph node involvement, compared to 11 of 101 (11%) without baseline uptake.3 Dr. Shariat noted that the performance of PET/CT in evaluating lymph node involvement in patients receiving neoadjuvant pembrolizumab does not justify its routine use in cN0 muscle-invasive bladder cancer patients.
Do the results of FDG-PET/CT change treatment recommendations? In 2022, Voskuilen et al. published the results of a retrospective analysis of 711 patients who underwent both a contrast-enhanced CT and PET/CT. FDG-PET/CT resulted in the clinical stage being altered in 26% of patients, with the recommended treatment strategy changing for 18% of patients. Notably, 8.1% of patients had false positive secondary findings.4FDG-PET/CT
What about FDG-PET/MRI? This imaging modality is an option for patients who cannot receive contrast. It combines the benefits of MRI with functional imaging. In a retrospective analysis of 15 patients with muscle-invasive, locally advanced, and metastatic bladder cancer, Civelek et al. demonstrated that FDG-PET/MRI performed for surveillance or re-staging results in a 36% improvement in lesion visibility, compared to conventional imaging with CT.FDG-PET/MRI performed for surveillance or re-staging results in a 36% improvement in lesion visibility, compared to conventional imaging with CT
Based on the current evidence, the following recommendations have been made by these governing bodies:

  • sEAU: “FDG-PET/CT can provide additional information to guide treatment (2b)”.
  • National Comprehensive Cancer Network (NCCN): “FDG-PET/CT (category 2B) may be useful in selected patients with ≥cT2 disease and may change treatment in patients with ≥cT3 disease”.
  • The National Institute for Health and Care Excellence: “FDG-PET/CT can be considered for people with MIBC or high-risk NMIBC before radical treatment if there are indeterminate findings on CT or MRI, or a high risk of metastatic disease (for example, T3b disease)”.

What are the limitations of FDG-PET/CT?

  • The reported diagnostic accuracy of FDG-PET/CT varies across studies. This is likely secondary to numerous factors:
    • Different methods for evaluating scans (qualitative versus quantitative, different SUV cut-offs)
    • Differences in labeling of suspicious lymph nodes (8 versus 10 mm, morphologic features)
    • Pathology as a reference test (in >10% of cases, tumor-positive lymph nodes are located outside the pelvic lymph node template)
    • Positive lymph nodes may be missed by histopathologic examination
  • False positive findings   shift from potentially curative to palliative treatment
  • Costs and financial burden

Are there novel PET-based imaging modalities emerging in this setting? Fibroblast activation protein (FAP) is highly expressed in the stroma of a variety of human cancers, including bladder cancer. 68Ga-FAPi-46 PET biodistribution across multiple cancers is strongly correlated with FAP tissue expression. This has led to the exploration of FAPi PET as a pan-cancer imaging biomarker for FAP expression and as a stratification tool for FAP-targeted therapies. In 2022, Novruzov et al. published a retrospective analysis of 8 patients with bladder cancer, 7 of whom underwent both [68Ga]FAPi and [18F]FDG-PET/CT scans within a median of five days. [68Ga]FAPi-PET/CT demonstrated significantly higher uptake compared to [18F]FDG PET/CT with higher mean SUVmax (8.2 vs. 4.6; p=0.01). Furthermore, [68Ga]FAPi detected 30% additional lesions missed by [18F]FDG. The tumor background ratio demonstrated favorable uptake for [68Ga]FAPi in comparison to [18F]FDG.6  TRACER BIODISTRIBUTION
Another exciting imaging modality emerging in this setting is 68Ga-N188 PET targeting nectin-4, a tumor-associated antigen found on the surface of most urothelial carcinoma cells. Enfortumab vedotin is a nectin-4 targeting antibody-drug conjugate approved for treating advanced urothelial carcinoma. A PET imaging method to noninvasively quantify nectin-4 expression level would potentially help predict treatment responders to enfortumab vedotin. 68Ga-N188 was designed as a bicyclic peptide-based nectin-4 targeting radiotracer and was shown to have a high affinity to nectin-4 in pre-clinical models. In a translational study of 14 patients with advanced urothelial carcinoma and two healthy volunteers, a clear correlation between the PET SUV value and nectin-4 expression was observed, supporting the application of 68Ga-N188 PET as a companion diagnostic tool for optimizing treatments that target nectin-4.7
68Ga-N188 PET targeting nectin-4
Another emerging tool is 68Zr-atezolizumab PET, which may be used as a non-invasive approach to assess clinical response to PD-L1 blockade across various malignancies. Early data suggests that the tracer uptake may be a strong predictor of response to atezolizumab treatment.8
 Early data suggests that the tracer uptake may be a strong predictor of response to atezolizumab treatment
Dr. Shariat noted that future applications of PET imaging in muscle-invasive bladder cancer in the future may include the following:

  • Diagnosis (disease classification)
  • Aid in management (staging, prognosis, prediction)
  • Guide targeted therapy (theranostics)

PET imaging in muscle-invasive bladder cancer in the future
He concluded his presentation noting the following:

  • The sensitivity of FDG-PET/CT for the detection of lymph node disease is superior to CT
  • The value of FDG-PET/CT at initial diagnosis is promising
  • FDG-PET/MRI may be an option for patients who cannot receive contrast
  • Exploration of new tracers beyond FDG is ongoing and initial results are promising
  • Improved imaging in muscle-invasive bladder cancer may allow for the avoidance of under and over-treatment, tailoring the right amount of ‘correct’ treatment to each person.

Presented by: Professor Sharokh Shariat, MD, Chairman, Department of Urology, Medical University of Vienna, Vienna General Hospital, Vienna, Austria

Written by: Rashid Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2024 European Association of Urology (EAU) annual congress, Paris, France, April 5th – April 8th, 2024

References:
  1. Ha HK, Koo PJ, Kim S, et al. Diagnostic Accuracy of F-18 FDG PET/CT for Preoperative Lymph Node Staging in Newly Diagnosed Bladder Cancer Patients: A Systematic Review and Meta-Analysis. Oncology. 2018;95(1): 31-38.
  2. Vind-Kezunovic S, Bouchelouche K, Ipsen P, et al. Detection of Lymph Node Metastasis in Patients with Bladder Cancer using Maximum Standardised Uptake Value and 18F-fluorodeoxyglucose Positron Emission Tomography/Computed Tomography: Results from a High-volume Centre Including Long-term Follow-up. Eur Urol Focus. 2019;5(1): 90-96.
  3. Marandino L, Capozza A, Bandini M, et al. [18F]Fluoro-Deoxy-Glucose positron emission tomography to evaluate lymph node involvement in patients with muscle-invasive bladder cancer receiving neoadjuvant pembrolizumab. Urol Oncol. 2021;39(4):235.e15-235.e21.
  4. Voskuilen CS, van Gennep EJ, Einerhand SMH, et al. Staging 18F-fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Changes Treatment Recommendation in Invasive Bladder Cancer. Eur Urol Oncol. 2022;5(3): 366-369.
  5. Civelek AC, Niglio SA, Malayeri AA, et al. Clinical value of 18FDG PET/MRI in muscle-invasive, locally advanced, and metastatic bladder cancer. Urol Oncol. 2021;39(11): 787.e17-787.e21.
  6. Novruzov E, Dendl K, Ndlovu H, et al. Head-to-head Intra-individual Comparison of [68Ga]-FAPI and [18F]-FDG PET/CT in Patients with Bladder Cancer. Mol Imaging Biol. 2022;24(4):651-658.
  7. Duan X, Xia L, Zhang Z, et al. First-in-Human Study of the Radioligand 68Ga-N188 Targeting Nectin-4 for PET/CT Imaging of Advanced Urothelial Carcinoma. Clin Cancer Res. 2023;29(17):3395-3407.
  8. Bensch F, van der Veen EL, Lub-de Hooge MN, et al. 89Zr-atezolizumab imaging as a non-invasive approach to assess clinical response to PD-L1 blockade in cancer. Nat Med. 2018;24(12): 1852-1858.