Elsevier

European Urology Focus

Volume 7, Issue 5, September 2021, Pages 1092-1099
European Urology Focus

Urothelial Cancer
Incidence and Clinical Impact of Inflammatory Fluorodeoxyglucose Positron Emission Tomography Uptake After Neoadjuvant Pembrolizumab in Patients with Organ-confined Bladder Cancer Undergoing Radical Cystectomy

https://doi.org/10.1016/j.euf.2020.10.003Get rights and content

Abstract

Background

Data regarding the incidence and prognostic impact of immune-related imaging changes, assessed by 18[F] fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) scan, in patients receiving immune-checkpoint inhibitors (ICIs) are lacking. We relied on the population of patients enrolled in the PURE-01 study to evaluate such changes.

Objective

To evaluate the role of PET/CT to visualize the immune-related adverse events (irAEs) following pembrolizumab.

Design, setting, and participants

From February 2017 to August 2019, in 103 patients with nonmetastatic, clinical T2–4aN0M0 bladder cancer, PET/CT scan was performed before and after neoadjuvant pembrolizumab (N = 206 scans), before radical cystectomy.

Intervention

PET/CT before and after neoadjuvant pembrolizumab, before radical cystectomy.

Outcome measurements and statistical analysis

We analyzed the occurrence of irAEs, evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, against the development of inflammatory FDG uptake described at PET/CT (irAEs + PET/CT). Logistic regression analyses evaluated the association between irAEs + PET/CT and the pathological response to pembrolizumab. Kaplan-Meier curves tested their association with progression-free survival (PFS) after pembrolizumab and radical cystectomy.

Results and limitations

Forty patients (39%) developed irAEs + PET/CT in several target organs. The most frequent target organs were the thyroid (N = 18), stomach (N = 14), mediastinal lymph nodes (N = 9), and lung (N = 5). These changes were clinically evident in 18 (45%) and were not associated with the pathological response, neither in terms of complete response (ypT0N0, p = 0.07) nor as downstaging to ypT≤1N0 disease (p = 0.1), although ypT0N0 responses were numerically more frequent in patients with irAEs+ PET/CT (47.5% vs 32%). Furthermore, irAE+ PET/CT events were associated with longer, not statistically significant, 24-mo PFS: 88.3% versus 76.5% (p = 0.5). Our results warrant further validation in larger datasets.

Conclusions

We presented unique surrogate data of PET/CT that could help improve our understanding of nonclinically evident effects of ICI administration, especially in patients at the early disease stage.

Patient summary

We evaluated the utility of PET/CT to visualize the occurrence of inflammatory changes after pembrolizumab in patients with localized bladder cancer without metastases. After immunotherapy, 39% of the patients developed 18[F] fluorodeoxyglucose uptake consistent of inflammatory changes. Overall, our data improve our knowledge on the effects induced by immunotherapy, which may have a clinical impact at longer follow-up.

Take Home Message

● In the PURE-01 study, T2–4N0M0 muscle-invasive bladder cancer patients were staged with fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) before and after pembrolizumab.

● PET/CT after pembrolizumab revealed inflammatory FDG uptake in 39% of patients, but only 45% of these cases of uptake corresponded to clinically evident adverse events.

● The development of inflammatory uptake was associated with a higher pathological complete response rate and longer progression-free survival, although these differences were not statistically significant.

Introduction

In patients with muscle-invasive, nonmetastatic (T2–4N0M0) bladder cancer (MIBC), standard radiological methods to stage the disease for treatment planning are represented by contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) scan, which are biased by well-documented limitations in the assessment of tumor infiltration within the bladder wall [1], [2], [3]. These limitations are well described in many radical cystectomy (RC) series [4], [5], [6], [7], [8], [9].

The role of [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT for the evaluation of pelvic lymph node metastases in MIBC is also controversial, and studies evaluating patients undergoing neoadjuvant chemotherapy (NAC) and RC or RC alone reported conflicting results in terms of prediction ability of the pathological status of pelvic lymph nodes, especially in patients presenting with a baseline clinical N0 stage [10], [11], [12], [13].

Furthermore, the advances in neoadjuvant therapy of MIBC, with the use of novel experimental therapies within clinical trials, will further raise the complexity of response assessment based on the unknown effects of these novel compounds on the avidity of PET tracers. Such developments are primarily involving the administration of immune-checkpoint inhibitors as backbone therapy. Following the results of the pivotal PURE-01 trial, added to those from ABACUS and other studies, a plethora of clinical trials are challenging the MIBC space, variously combining NAC with immune-checkpoint inhibitors or offering chemotherapy-free combinations, depending on the eligibility for cisplatin [14], [15], [16], [17]. In this context, PET/CT imaging could be useful not only for staging the lymph nodes and response evaluation, but also for visualization of any overt immune-related adverse events (irAEs) after treatment. To date, no data on PET/CT findings are available in the context of nonmetastatic, localized solid tumors receiving single-agent immune-checkpoint inhibitors. Among the planned secondary endpoints of the PURE-01 study, there were several translational imaging endpoints. The objective of the present study was to assess the ability of FDG-PET/CT to visualize the development of irAEs in patients enrolled in PURE-01 and to evaluate their association with clinical outcomes.

Section snippets

Study design and description of the study population

Eligible patients had a confirmed diagnosis of MIBC, a clinical-stage (c) T2-4aN0M0, and were scheduled for pembrolizumab and RC regardless of their cisplatin eligibility. Three courses of pembrolizumab, 200 mg intravenously every 3 wk, were administered prior to RC. Patients were staged with PET/CT scan, contrast-enhanced thorax-abdomen CT scan, and bladder multiparametric MRI during screening and after treatment, before RC. The results of the latter assessment, as well as all the remaining

Patient and disease characteristics

From February 2017 to August 2019, 124 patients were enrolled and treated with pembrolizumab (Fig. 1). The median follow-up was 23 mo (interquartile range [IQR]: 15–29). A total of 103 patients had paired pre- and post-therapy PET/CT scans available for the study purposes (206 total scans). Their baseline clinical characteristics are summarized in Table 1. The median time between baseline PET/CT and RC was 70 d (IQR: 64–82), and the time between postpembrolizumab PET/CT and RC was 17 d (IQR:

Discussion

To the best of our knowledge, the current study is the first to prospectively report the performance of PET/CT in terms of the detection rate, clinical value, and prognostic impact of inflammatory FDG uptake after immune-checkpoint inhibition. This assessment was also made in the unique model of organ-confined nonmetastatic bladder cancer patients receiving three courses of pembrolizumab before RC. This model has certainly the advantage of allowing investigators to assess the side effects of

Conclusions

In summary, although the routine incorporation of PET/CT scan to stage patients with nonmetastatic MIBC is still a matter of clinical debate and generally not recommended in guidelines, its surrogate importance in the PURE-01 trial was represented by the ability to visualize subclinical inflammatory changes in several target organs after a short course of single-agent pembrolizumab. This observation could be helpful for ensuring appropriate clinical monitoring of patients and tailoring the

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