Can PET-CT improve the staging and outcome of patients with muscle-invasive bladder cancer?

Patients with non-metastatic muscle-invasive bladder cancer (MIBC) receive neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC). Alternatively, patients are treated with trimodality therapy. For locally advanced MIBC, adjuvant immunotherapy is further indicated (1,2). Despite treatment intensification over time, the prognosis remains poor with overall survival at 5 years of <60% (3). Lack of improvement in outcome might be due to an inaccurate staging of patients at the time of diagnosis. According to guidelines, conventional imaging [i.e., computed tomography (CT) and magnetic resonance imaging (MRI)] is recommended for the primary staging of patients with MIBC, and fluorodeoxyglucose-positron emission tomography-CT (FDG-PET-CT) can be used to guide treatment, although its value is still highly debated (2).

Multiple trials have shown that PET-CT has a higher diagnostic accuracy than CT or MRI for local and distant staging of MIBC patients (4-6).

A systematic review reported a pooled sensitivity of 58% [95% confidence interval (CI): 51–64%] and specificity of 89% (95% CI: 82–94%) for lymph node staging with PET-CT/MRI. For distant metastases, a pooled sensitivity and specificity for PET-CT/MRI of 89% (95% CI: 61–98%) and 95% (95% CI: 80–99%), respectively was found. Within this systematic review, no radiotracer outperformed another (4).

Fibroblast activation protein (FAP) is a type II transmembrane serine protease that is upregulated on fibroblasts at sites of active tissue remodeling. High expression of FAP is also found in solid tumors which makes it an attractive target for molecular imaging (7-9). Hagens et al. suggested that FAP inhibitor (FAPI) radiotracers are more accurate for local and distant staging of patients with genitourinary cancers. However, the overall level of evidence remains low (10). Although ⁶⁸Ga-FAP-PET can potentially refine the staging of MIBC patients, some words of caution should be made.

First, while immunohistochemical studies showed high expression of FAP in urothelial cancer, FAP is not specific for urothelial carcinomas. FAP overexpression is seen in different other tumor types, such as gastrointestinal malignancies, as well as several benign conditions (7-9).

Second, like other tracers, FAP-targeting radiotracers are excreted through the urinary tract which hampers the visualization of primary tumors in the bladder and upper urinary tract. Also, the superiority of FAPI-based PET radiotracers over other tracers for lymph node staging and detection of bone metastases is still unclear.

In the study of Koshkin et al., the potential of ⁶⁸Ga-FAP-2286 PET imaging in the staging of MIBC is further explored (11). The authors concluded that the largest advantage of ⁶⁸Ga-FAP-2286 PET is the earlier detection of smaller lesions (i.e., lymph nodes <1 cm) compared to conventional imaging. The authors also suggest that ⁶⁸Ga-FAP-2286 PET outperforms FDG-PET-CT due to an improved tumor-to-background ratio and finer resolution of nodal disease.

Although recognized by the authors, it is important to point out that this is a small study in a heterogeneous MIBC patient group, including patients with metastatic and localized disease. In the localized MIBC group, histological confirmation of disease was aimed for but was only reported in 4 out of 7 patients with positive ⁶⁸Ga-FAP-2286 PET scan, resulting in a sensitivity of ⁶⁸Ga-FAP-2286 PET of 57%. Also, in the recent paper of Unterrainer et al., the sensitivity of ⁶⁸Ga-FAPI-46 PET/CT was 57% (12). This is comparable but not superior to the sensitivity data reported with other PET-CT tracers (both ¹⁸F-FDG or C11-choline). It is unclear whether the remaining 6 patients with negative ⁶⁸Ga-FAP-2286 PET imaging in the localized cohort had pathological confirmation of absence of nodal invasion.

In the presented study, ⁶⁸Ga-FAP-2286 PET was performed before NAC and two patients had no evidence of disease (pathological T0N0M0) after NAC and surgery (11). It would have been interesting to have a ⁶⁸Ga-FAP-2286 PET during and after completing NAC to see whether imaging would have become negative afterward. Imaging might have an important role in the treatment management of MIBC patients and could be used to distinguish patients who benefit from NAC from those who do not.

It has been suggested that patients with residual disease at RC after NAC have worse overall survival and cancer-specific survival when compared to matched patients who did not receive NAC (13,14). Predicting tumor response on NAC enables us to determine whether a patient should be referred for early RC, and whether a patient is an optimal candidate for bladder-preserving therapies, such as trimodality therapy. The value of PET-CT and MRI in predicting treatment response has been studied and promising results have been reported for both imaging modalities although further research is needed (15,16).

Finally, in this study of Koshkin et al., discordancy between conventional imaging and Ga-FAP-2286 PET CT was seen in 8 out of 13 patients (62%) in the localized MIBC group, resulting in a change in treatment plan in 3 of them (38%) (11).

Undoubtedly, better imaging modalities will lead to better risk classification of MIBC patients. But, as for other tumor types, it is unclear how additional information, from PET-CT, should be incorporated into the treatment approach of our MIBC patients. The EFFORT study is an ongoing Belgian multicentric trial that evaluates the impact of treatment intensification based on ¹⁸F-FDG-PET-CT (17). Patients included in the EFFORT trial are all non-metastatic MIBC patients on conventional imaging and are treated radically. All patients receive an ¹⁸F-FDG-PET-CT before and after NAC. Based on ¹⁸F-FDG-PET-CT patients are classified as truly non-metastatic (group 1), oligometastatic (group 2) or polymetastatic (group 3). For the latter two groups treatment intensification is performed with a metastasis-directed therapy or initiation of adjuvant immunotherapy for patients categorized in groups 2 and 3 respectively (17). This trial is still in the recruiting phase. Results are awaited to evaluate the impact of more precise imaging modalities and treatment adjustments on oncological outcomes.

To conclude, although this study adds to the literature evaluating the potential of PET-CT imaging in the staging of MIBC, further prospective trials are eagerly awaited to define the place of FAPI-PET-CT in staging and treatment management.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-115/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-115/coif). V.F. reports grant from Kom op Tegen Kanker for the ongoing EFFORT-study, consulting fees and speaker fees from Janssen. D.D.M. reports support for travel and attending meetings from Ipsen, MSD, Bayer, and is on the Advisory Board for Johnson & Johnson (Janssen), Astellas. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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References

1. Powles T, Bellmunt J, Comperat E, et al. Bladder cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol 2022;33:244-58. [Crossref] [PubMed]
2. Alfred Witjes J, Max Bruins H, Carrión A, et al. European Association of Urology Guidelines on Muscle-invasive and Metastatic Bladder Cancer: Summary of the 2023 Guidelines. Eur Urol 2024;85:17-31. [Crossref] [PubMed]
3. Adjuvant Chemotherapy for Muscle-invasive Bladder Cancer. A Systematic Review and Meta-analysis of Individual Participant Data from Randomised Controlled Trials. Eur Urol 2022;81:50-61. [Crossref] [PubMed]
4. Fonteyne V, De Man K, Decaestecker K, et al. PET–CT for staging patients with muscle invasive bladder cancer: is it more than just a fancy tool? Clin Transl Imaging 2020;9:83-94. [Crossref]
5. Al-Zubaidi M, Ong K, Viswambaram P, et al. Comparing fluorodeoxyglucose positron emission tomography with computed tomography in staging for nodal and distant metastasis in urothelial/bladder cancer. BJUI Compass 2024;5:473-9. [Crossref] [PubMed]
6. Einerhand SMH, Zuur LG, Wondergem MJ, et al. The Implementation of FDG PET/CT for Staging Bladder Cancer: Changes in the Detection and Characteristics of Occult Nodal Metastases at Upfront Radical Cystectomy? J Clin Med 2023;12:3367. [Crossref] [PubMed]
7. Fitzgerald AA, Weiner LM. The role of fibroblast activation protein in health and malignancy. Cancer Metastasis Rev 2020;39:783-803. [Crossref] [PubMed]
8. Greimelmaier K, Klopp N, Mairinger E, et al. Fibroblast activation protein-α expression in fibroblasts is common in the tumor microenvironment of colorectal cancer and may serve as a therapeutic target. Pathol Oncol Res 2023;29:1611163. [Crossref] [PubMed]
9. Watabe T, Giesel FL. Fibroblast Activation Protein Inhibitor PET/CT in Gastric Cancer. PET Clin 2023;18:337-44. [Crossref] [PubMed]
10. Hagens MJ, van Leeuwen PJ, Wondergem M, et al. A Systematic Review on the Diagnostic Value of Fibroblast Activation Protein Inhibitor PET/CT in Genitourinary Cancers. J Nucl Med 2024;65:888-96. [Crossref] [PubMed]
11. Koshkin VS, Kumar V, Kline B, et al. Initial Experience with 68Ga-FAP-2286 PET Imaging in Patients with Urothelial Cancer. J Nucl Med 2024;65:199-205. [Crossref] [PubMed]
12. Unterrainer LM, Eismann L, Lindner S, et al. [68 Ga]Ga-FAPI-46 PET/CT for locoregional lymph node staging in urothelial carcinoma of the bladder prior to cystectomy: initial experiences from a pilot analysis. Eur J Nucl Med Mol Imaging 2024;51:1786-9. [Crossref] [PubMed]
13. van Ginkel N, Hermans TJN, Meijer D, et al. Survival outcomes of patients with muscle-invasive bladder cancer according to pathological response at radical cystectomy with or without neo-adjuvant chemotherapy: a case-control matching study. Int Urol Nephrol 2022;54:3145-52. [Crossref] [PubMed]
14. Bhindi B, Frank I, Mason RJ, et al. Oncologic Outcomes for Patients with Residual Cancer at Cystectomy Following Neoadjuvant Chemotherapy: A Pathologic Stage-matched Analysis. Eur Urol 2017;72:660-4. [Crossref] [PubMed]
15. Soubra A, Gencturk M, Froelich J, et al. FDG-PET/CT for Assessing the Response to Neoadjuvant Chemotherapy in Bladder Cancer Patients. Clin Genitourin Cancer 2018;16:360-4. [Crossref] [PubMed]
16. Woo S, Becker AS, Das JP, et al. Evaluating residual tumor after neoadjuvant chemotherapy for muscle-invasive urothelial bladder cancer: diagnostic performance and outcomes using biparametric vs. multiparametric MRI. Cancer Imaging 2023;23:110. [Crossref] [PubMed]
17. Verghote F, Poppe L, Verbeke S, et al. Evaluating the impact of 18F-FDG-PET-CT on risk stratification and treatment adaptation for patients with muscle-invasive bladder cancer (EFFORT-MIBC): a phase II prospective trial. BMC Cancer 2021;21:1113. [Crossref] [PubMed]