[18F]FDG PET/CT can trigger relevant oncological management changes leading to favorable outcome in iodine-negative thyroid cancer patients

Background In patients with iodine-negative thyroid cancer (TC), current guidelines endorse an [18F]FDG PET/CT to identify dedifferentiated sites of disease. We aimed to determine the rate of oncological management changes triggered by such a molecular imaging approach, along with the impact on outcome. Methods 42 consecutive patients with negative findings on [131I] whole body scan were scheduled for [18F]FDG PET/CT and treatment based on PET results were initiated. To determine the impact on oncological management, we compared the therapeutic plan prior to and after molecular imaging. Based on imaging follow-up, the rate of controlled disease (CD, defined as stable disease, complete or partial response) was also recorded, thereby allowing to assess whether [18F]FDG-triggered management changes can also lead to favorable outcome. Results We observed no alterations of the treatment plan in 9/42 (21.4%) subjects (active surveillance in 9/9 [100%]). Oncological management was changed in the remaining 33/42 (78.6%; systemic treatment in 9/33 [27.3%] and non-systemic treatment in 24/33 [72.7%]). Among patients receiving non-systemic therapy, the following changes were noted: surgery in 20/24 (83.3%) and radiation therapy in 4/24 (16.7%). In the systemic group, tyrosine kinase inhibitor (TKI) was prescribed in 8/9 (88.9%), while radioiodine therapy based on a TKI-mediated redifferentiation approach was conducted in 1/9 (11.1%). In 26 subjects with available follow-up, rate of CD was 22/26 (84.6%) and among those, 15/22 (68.1%) had experienced previous management changes based on PET/CT findings. Conclusions In subjects with iodine-negative TC, [18F]FDG PET/CT triggered relevant management changes along with disease control in the vast majority of patients. As such, in dedifferentiated TC, [18F]FDG PET/CT may serve as a relevant management tool and therapeutic decision-aid in the clinic.


Introduction
Current guidelines endorse radioiodine therapy (RIT) after thyroidectomy in patients diagnosed with differentiated thyroid cancer (TC) and such a sequential therapeutic approach provides favorable outcome along with complete remission (CR) in most of the patients [1].A [ 131 I] whole body scan (WBS) may rule out thyroid remnants or widespread metastatic disease.Downregulation of the sodiumiodine symporter, however, may then cause a [ 131 I] loss in target lesions [2], indicative for dedifferentiation of disease.This clinical scenario, however, may then pose a challenge for the treating endocrinologist or nuclear medicine specialist.As such, negative WBS then requires further diagnostic work-up to identify active sites of disease [1].For instance, conventional imaging including computed tomography (CT) or magnetic resonance imaging (MRI) have yielded mixed results in detecting dedifferentiating lesions [3].[ 18 F]FDG, however, has also been applied in such patients and has provided excellent read-out capabilities due to increased glucose consumption in TC lesions with [ 131 I] loss [4].In this regard, a growing body of evidence has already demonstrated the clinical value of a dual-radiotracer strategy of [ 131 I] WBS / [ 18 F]FDG PET/CT.Among others, Palmedo et al. reported on a diagnostic accuracy of more than 90% in this patient population [4], while quantitative parameters derived from [ 18 F]FDG also had prognostic ability for outcome [5,6].Given those favorable diagnostic and prognostic performance, a recent study investigated the impact of [ 18 F]FDG on oncological management in iodine-negative TC patients and reported on 10/21 (48%) with altered treatment plan [4].However, in this previous investigation, the therapeutic armamentarium in dedifferentiated disease did not include tyrosine kinase inhibitor (TKI) or redifferentiation approaches for readministration of [ 131 I] at that time.Thus, in this previous study, the authors only reported on surgical intervention as management changes, i.e., alterations of the treatment plan were limited to non-systemic therapeutic changes [4].
In the present study, we aimed to determine the impact on oncological management of [ 18 F]FDG PET/CT in iodione-negative TC patients, particularly focusing on systemic treatment alterations (TKI, RIT after iodine uptake restoration) vs. non-systemic changes (surgery, external beam radiation [RTx]).

General
Due to the retrospective character, the local ethics committee at the University Hospital of Würzburg waived the need for further approval (No. 20230721 01).A previous case reported on one subject of this cohort which was scheduled for a redifferentiation approach, i.e., RIT was performed due to restored radioiodine uptake mediated by previous TKI intake [7].I]) and showed no relevant uptake on WBS along with increasing tumor marker thyroglobulin (TG).[ 18 F]FDG PET/CT for restaging was then performed as part of clinical routine follow-up.All subjects included in the study gave informed consent for procedures.A supplementary table provides a detailed overview on previous therapies and TG at time of scan.

Imaging procedures
[ 18 F]FDG PET/CT low dose technique was performed in all patients with a Siemens Biograph mCT 64 or 128 (Siemens Healthineers, Erlangen, Germany) scanner.The imaging procedure was performed 60 min after the injection of approximately 292 ± 41 MBq of [ 18 F]FDG.A scan of the whole body (from the top of the skull to the proximal thigh) was performed.The section thickness of the PET/CT was 5 mm.All PET images were iteratively reconstructed in accordance with the manufacturer's instructions (Siemens Healthineers, Erlangen, Germany).

Change in oncological management based on [ 18 F] FDG PET/CT
Treatment plans right before and after [ 18 F]FDG PET/CT were retrieved from our medical archive.Treatment alterations were either classified as systemic (TKI [including dose alterations], redifferentation approach using RIT after TKI intake) or non-systemic therapy (surgery, RTx).Surgical approaches were also divided into cervical vs. thoracic procedures.

Impact of management change on disease control
To determine the impact of management change on CD, the first follow-up imaging (conducted within one year) after [ 18 F]FDG PET/CT was assessed.We applied RECIST criteria 1.1.Stable, partial, or complete response was then summarized as CD [8,9] .

Statistical analysis
Descriptive statistics are indicated as mean ± SD.We used Excel for Windows 2016 (Microsoft, Redmond, WA, USA) and GraphPad Prism Software (9.3.1;La Jolla, CA, USA).

[ 18 F]FDG PET/CT identified sites of disease in all patients
On a patient-based level, [ 18   1).
[ 18 F]FDG PET/CT led to change in oncological management in more than 78% We observed no changes of the treatment plan after [ 18 F] FDG PET/CT in 9/42 (21.4%) subjects and in those individuals, active surveillance was conducted (9/9 [100%]).

Discussion
In patients with dedifferentiated TC scheduled for [ 18 F]FDG after the first negative WBS, PET/CT led to management changes in more than 78% of the patients.Of those subjects, the majority was allocated to non-systemic alterations, mainly including surgical interventions.After PET/CT, however, approximately one-fourth of the subjects were also treated systemically using TKI (or TKI in combination with RIT).Of note, the [ 18 F]FDG-triggered change in management then also led to disease control in more than 68% of the subjects.Taken together, even with an increasing therapeutic armamentarium in iodine-negative TC patients [10], [ 18 F]FDG PET/CT provided crucial therapeutic decision-aid to identify the most appropriate treatment.Of note, this applied to subjects with limited (scheduled for surgery or RTx) and patients with widespread disease (triggering TKI prescription or TKI-mediated RIT).
Loss of sodium-iodine transporter in TC may pose a challenge, as RIT no longer provides anti-tumor efficacy and thus, in patients with negative WBS with or without rising TG, [ 18 F]FDG may identify dedifferentiating tumor lesions [4].Previous reports have reported on excellent diagnostic accuracy [4], but information on clinical relevance is rather limited.In this regard, a previous investigation published in 2006 showed that PET/CT can change management in a substantial fraction of patients, mainly surgical interventions.In the last two decades, a plethora of novel therapies have entered the clinical arena [10], including lenvatinib in iodine-refractory TC with response rates of almost 65% when compared to placebo [11].Moreover, favorable outcome has also been reported using pazopanib or sorafenib [12,13], which even led to approval by respective agencies [14].As such, given the beneficial evidence of such oral kinase inhibitors in iodine-refractory subjects in recent years, we aimed to determine whether [ 18 F]FDG is still useful to guide the treating physician towards the most appropriate next therapeutic step beyond surgical procedures.We recorded management alterations in >78% of the subjects, with disease control in 68.1% that had experienced previous changes of the treatment plan.This is slightly increased when compared to the findings of Palmedo et al. (48%) [4] and may be partially explained by the improved scanner technology in our study (Biograph mCT 64 or 128) along with improved read-out.Systemic treatment alterations were rather less frequent in our analysis and included use of TKI, but also redifferentiation approaches, i.e., restoration of radioiodine uptake due to TKI-mediated modulation of the sodium-iodine symporter in TC cells [15].Due to the increasing use of such sophisticated therapeutic approaches of target re-activation [7,16], our study also provides a hint that [ 18 F]FDG could serve as a decision-aid to identify patients eligible for such a salvage approach.
Of note, comparable to previous work [4], we also recorded surgery as the most frequent intervention after [ 18 F]FDG and those findings are most likely due to the fact that patients were included right after the first negative WBS (i.e., at an early stage of re-differentiating disease).As such, future studies may also investigate individuals at later stage, which may then also  Nonetheless, the present and previous studies indicate that this radiotracer is beneficial in subjects presenting with iodinenegative WBS.This applies in particular to limited cervical disease, where [ 18 F]FDG can then precisely localize metastatic LN, thereby guiding the endocrine surgeon or otorhinolaryngologist in pre-operative planning.Of note, a substantial fraction of individuals in our study also presented with thoracic findings revealed by molecular imaging, which then also triggered interventions by thoracic surgery in 40% (including dissection of mediastinal LN and lung metastases).Those findings may be of relevance, as a previous study also reported that loss of radioiodine avidity in pulmonal lesions is an independent predictor of poor outcome, thereby emphasizing the importance of an accurate thoracic read-out by [ 18 F]FDG PET/CT in those high-risk patients [17].
Prospective studies are needed to corroborate our preliminary findings.Future analyses, however, may also consider to repeat our investigation in a larger number of patients, by pooling data from multiple centers or by using other, sensitive PET agents, e.g., [ 18 F]tetrafluoroborate [18,19] or theranostic agents also used in such a patient population, e.g., prostate-specific membrane antigentargeted PET/CT [20].

Conclusions
In patients with dedifferentiated TC scheduled for [ 18 F]FDG after the first negative WBS, PET/CT led to management changes in the vast majority of patients, including systemic (TKI, RIT after re-differentiation) and non-systemic treatment changes (thoracic/cervical surgery, RTx).Those alterations of the treatment plan achieved controlled disease in more than 68% of the patients.The high rate of PET/CTtriggered surgical interventions indicate that [ 18 F]FDG may be particularly useful to precisely localize limited cervical or widespread thoracic disease, thereby also serving as a valuable pre-operative planning tool.